Author: Ben Debski

Eisai’s eribulin added an average of two and a half months to the lives of patients dying of breast cancer, which is a big improvement in such seriously ill cancer patients, the international team of researchers said.

The results of the Phase III trial, presented to a meeting of the American Society of Clinical Oncology in Chicago, have been anticipated after Eisai was given priority review June 1 for US Food and Drug Administration approval of the drug.

“This is potentially practice changing,” ASCO president Dr Douglas Blayney said in a telephone interview.

Dr Christopher Twelves of St James Hospital in Leeds in Britain and an international team studied 762 breast cancer patients with different types of tumor.

All had cancer that had spread and been through at least two rounds of chemotherapy. Two-thirds got two doses of eribulin while getting standard treatment, usually with one other chemotherapy drug but occasionally with just supportive care to treat pain and other symptoms.

The other third got either a third round of chemotherapy or supportive care. “Once this treatment fails, the patient often died,” Blayney said.

The patients given eribulin did considerably better, the researchers told the meeting. The eribulin patients lived a median of 13 months, compared to just under 11 months for patients who did not get eribulin.

Longer lives
Most cancer trials look for what is called progression-free survival, meaning the doctors are looking to see if the tumors start growing back, or sometimes just response rate, to see if the tumors shrink at all.

This one looked to see how long the patients actually lived.

“This study is the first to compare overall survival with this new chemotherapeutic agent to real-life choices in heavily pretreated patients with metastatic breast cancer,” Twelves and colleagues said in their written presentation.

The drug works on the same principle, but with a slightly different mechanism, as older cancer drugs called taxanes and is infused intravenously.

Other experts said eribulin could be one of the last new chemotherapy drugs, which typically target fast-growing cells that include tumors but also healthy cells.

“This is the era of targeted therapy. It’s not an era of chemotherapy,” said Dr Eric Winer of Harvard’s Dana-Farber Cancer Institute in Boston, who was not involved in the study.

“I don’t know that there are going to be many more chemotherapy agents approved for women with breast cancer. That said, this may be one of the last, and potentially provide women with an additional option and maybe an option to be used in combination with targeted therapies in the future.”

Three other studies presented to the meeting showed eribulin was effective and tolerated in a different group of patients with breast cancer, as well as colon cancer and urinary cancer patients.

Eisai has filed in Japan, the US and Europe for approval of eribulin. The company hopes it will become a blockbuster, with global earnings of $1bn a year.

“I think there is a reasonable chance that this drug will actually get approved,” Winer said. “There aren’t many drugs that show a survival advantage in this setting.”

Exact’s test is non-invasive and will be significantly less expensive than a colonoscopy, the current screening gold standard. As President and CEO Kevin Conroy explains in addition to saving lives, conservative estimates show a potential US market of more than $1bn.

Inside the laboratories bustling with activity at Exact Science’s
Madison, WI headquarters, my team’s mission is clear – to save lives by
making the detection of colorectal cancer patient-friendly and accurate.
Everyone who works at Exact Sciences knows the terrible statistics;
more than six hundred thousand people around the world die each year of
colorectal cancer. That’s the equivalent of fifteen hundred 747s
crashing with no survivors. The numbers are enormous, but each case also
represents a person, a parent, a spouse, a sibling, and that is
something that is never far from our minds.

Despite the enormous death toll from colorectal cancer, there is reason for hope. If detected at early stages before symptoms occur, cure rates are very high. And if pre-cancerous polyps can be detected, colorectal cancer can be effectively prevented. The tumour starts as a precancerous polyp, which typically grows over ten to 15 years before becoming a cancer. So, if such polyps can be detected, colorectal cancer can be prevented.

Today, more than half of all colorectal cancers are detected because the patient is experiencing symptoms. In most of these cases the tumours are at advanced stages, survival odds are decreased and treatment options are more costly and severe. The bottom line is that outcomes from this dreaded disease can be greatly improved with effective screening. We believe that a patient-friendly test that reliably detects cancers and pre-cancers will help save countless lives and create shareholder value in the process.

Recent data suggest that roughly 15 million colorectal cancer screening tests are performed each year in the US, which is just a fraction of the nearly 100 million Americans who under the current guidelines should be screened.

Exact Sciences has developed an advanced, affordable and patient-friendly means of detecting colorectal cancer and pre-cancerous polyps.  In fact, it is the only non-invasive way to reliably detect pre-cancers. Unlike colonoscopy, the Exact test requires no bowel preparation or medication restrictions. Patients will be able to use our test in the comfort and privacy of their own homes. There is no need for sedation or missed days of work. Access to the test will be virtually unlimited, as sample collection kits could be distributed to patients and returned to the laboratory by mail.

The Exact Sciences test is designed to detect altered DNA from pre-cancer and cancer, leading to early diagnosis and in many cases the actual prevention of colorectal cancer. By performing our test at regular intervals, most pre-cancers could be detected before cancer develops. As with the Pap smear test, which has nearly eliminated cervical cancer among those regularly screened, it is our ultimate goal to eradicate colorectal cancer with regular and widespread application of an effective and user-friendly screening tool.

We believe the market opportunity in the US alone is more than $1bn annually. This assumes only 30 percent of people over age 50 will receive one test every third year. We own exclusive rights to this test, which we fully expect will detect more than 85 percent of cancers and more than 50 percent of pre-cancers. There is no other test in molecular diagnostics that has as great a market potential as this one.

Currently, Exact Sciences is making tremendous progress toward bringing this test to patients.  Our scientists have been working in close collaboration with doctors at Mayo Clinic in Rochester, MN. In July, Exact Sciences released tissue data that showed using our unique combination of four methylated biomarkers we could detect 100 percent of both colorectal cancers and pre-cancers with 100 percent specificity.

We are unaware of any other markers or combination of markers that has achieved such complete discrimination. The early validation began this fall and we plan to begin our multi-site clinical trial in the second quarter of 2011 with a goal of submission to the Food and Drug Administration in 2012.

We plan to launch the product shortly after FDA approval. Exact Sciences is working with the Centers for Medicaid and Medicare Service to secure coverage of our test upon FDA approval. We are laying the groundwork to commercialise our test. There remain several significant tasks to complete before our test is launched, and these will be carefully planned and executed. The company has engaged key physicians, laboratorians, and payers.

These leaders continue to provide us with valuable insight into the market and how they expect it to change. We are coupling these important perceptions with a thorough review of several cancer screening success stories in our industry, including Digene and Cytyc.

Investors and analysts have been responding favourably to our focus and the preliminary scientific data we have been able to provide regarding our assay.  Piper Jaffray initiated coverage of Exact Sciences in June with an overweight rating.

“Our overweight rating reflects expectations for management’s successful execution of Exact’s next-generation colorectal cancer screening assay commercialisation strategy and we expect investors will be rewarded as near-term milestones are realied,” wrote Piper Jaffray Senior Research Analyst William Quirk. Four other analysts have also initiated coverage of Exact Sciences, each one listing the company as a buy for investors.

I am confident that Exact Sciences is on the right path toward successfully developing and marketing a non-invasive patient-friendly colon cancer screening test. And my confidence grows each time I speak with members of the Exact Sciences team, who have in a short time proven that they have the intellect, desire and commitment to achieve our plan. Working together, we can achieve our goal of reducing colorectal cancer incidence and mortality in the US and around the world.

Research into the effects of psychedelics, used in the past in psychiatry, has been restricted in recent decades because of the negative connotations of drugs, but the scientists said more studies into their clinical potential were now justified.

The researchers said recent brain imaging studies show that psychedelics such as lysergic acid diethylamide (LSD), ketamine and psilocybin – the psychoactive component in recreational drugs known as magic mushrooms – act on the brain in ways that could help reduce symptoms of various psychiatric disorders.

The drugs could be used as a kind of catalyst, the scientists said, helping patients to alter their perception of problems or pain levels and then work with behavioural therapists or psychotherapists to tackle them in new ways.

“Psychedelics can give patients a new perspective – particularly when things like suppressed memories come up – and then they can work with that experience,” said Franz Vollenweider of the Neuropsychopharmacology and brain imaging unit at Zurich’s University Hospital of Psychiatry, who published a paper on the issue in Nature Neuroscience journal.

Depending on the type of person taking the drug, the dose and the situation, psychedelics can have a wide range of effects, experts say, from feelings of boundlessness and bliss at one end of the spectrum to anxiety-inducing feelings of loss of control and panic at the other.

Low doses
Vollenweider and his colleague Michael Kometer, who also worked on the paper, said evidence from previous studies suggests such drugs might help ease mental health problems by acting on the brain circuits and neurotransmitter systems that are known to be altered in people with depression and anxiety.

But if doctors were to use them to treat psychiatric patients in future, it would be important to keep doses of the drugs low, and ensure they were given over a relatively short time period in combination with therapy sessions, they said.

“The idea is that it would be very limited, maybe several sessions over a few months, not a long-term thing like other types of medication,” Vollenweider said in a phone interview.

A small study published by US scientists found that an infusion of ketamine – an anaesthetic used legally in both human and veterinary medicine, but also abused by people who use it recreationally – can lift the mood within minutes in patients with severe bipolar depression.

Mental illnesses such as depression are a growing health problem around the world and Vollenweider and Kometer said many patients with severe or chronic psychiatric problems fail to respond to medicines like the widely-prescribed selective serotonin reuptake inhibitors, or SSRIs, like Prozac or Paxil.

“These are serious, debilitating, life-shortening illnesses, and as the currently available treatments have high failure rates, psychedelics might offer alternative treatment strategies that could improve the well-being of patients and the associated economic burden on patients and society,” they wrote.

Researchers said the find may help doctors to give more personalised care to transplant patients and to modify the amount of powerful immunosuppressant drugs they have to take to prevent their bodies from rejecting a new kidney.

The scientists, led by Maria Hernandez-Fuentes at King’s College London, studied various groups of kidney transplant patients in Europe, including 11 patients who had stopped taking their drugs after the transplant but did not reject the donor organ since they appeared to have a natural “tolerance” for it.

They carried out detailed tests of blood samples and found differences in the immune systems particular to these patients.

“We hope that now we can start to look at screening other patients to see if they also have similar markers in their blood,” said Rachel Hilton, a renal consultant at Guy’s Hospital in London and co-author of the study.

“There may be many more patients out there who potentially could reduce or stop their medication if we can screen them to see if their immune systems looks similar,” she said in a telephone interview.

Kidney transplants are the most common type of major organ transplant worldwide – around 1,550 are carried out in Britain and around 18,000 in the US every year. The average lifespan of a transplanted kidney is 12 years, rising to around 20 years in some cases if the kidney is from a living donor.

For many patients, a kidney transplant opens up a new life, but it also means they must take immunosuppressants – which have a wide-range of side effects – for the rest of their lives to make sure the new organ is not rejected.

Novartis’s Neoral, Myfortic and Sandimmune, Roche’s Cellcept, Pfizer’s Rapamune and Prograf from Astellas Pharma are among some of the leading branded drugs given to prevent transplanted organ rejection.

“If you’re on these transplant drugs for life, then you have the side effects for life as well as the benefits,” said Hilton.

“The main side effects are increased risk of infection and a higher risk of future cancers, so they are very undesirable side effects in both the short- and the long-term.”

The European team compared the 11 patients who had a natural tolerance of the new kidney against patients who were taking varying amounts of immunosuppressants, as well as patients who were taking the drugs but also showing signs of rejecting the donor organ, and a group of healthy volunteers.

They described what they found what as a “full set” of markers which made “tolerance fingerprint” in some patients.

The findings were later corroborated in another study by the Immune Tolerance Network in the US and both studies were published by the Journal of Clinical Investigation.

But the findings do not mean transplant patients should stop taking their medication without talking to a doctor.

“It is vitally important..that transplant recipients do not stop taking their immunosuppression on the back of these research findings,” Hilton said. “Any reduction in medication needs to be very carefully managed and clinically monitored.”

Franco Cappuccio, head of the WHO’s collaborating centre for nutrition, said voluntary moves by the food industry had brought some progress, but lawmakers should now harness the scientific evidence on salt and seek to change the tastes of nations.

“There is now a total acceptance that salt is bad for us, we eat far too much of it, and it should be reduced,” Cappuccio told reporters in an interview.

“So there is great scope now to consider a regulatory approach to reinforce and sustain the voluntary moves.”

But Cappuccio, a professor of cardiovascular medicine at Warwick University, where the WHO’s nutrition centre is based, said powerful lobbying from the food and drink industry, whose profits are swelled by added salt, have slowed efforts to bring consumption levels down.

Cutting salt intake substantially reduces blood pressure, helping to lower the risk of heart attacks and strokes. High blood pressure is ranked as the the world’s number one killer, accounting for 7.5 million deaths a year.

A 2007 study which analysed all the available evidence at the time found that reducing salt intake around the world by 15 percent could prevent almost nine million deaths by 2015.

Another study in March found that cutting salt intake by just 10 percent in the US could prevent hundreds of thousands of heart attacks and strokes over decades and save the government $32bn in healthcare costs.

There is little doubt that we eat too much salt. In Britain, average adult intake is around 8.6 grams per day, while in the US it is around 10 grams, almost twice the amount suggested by the WHO.

Even the WHO recommendation of five grams a day is far more than we actually need, which is only around 1.5 grams.

Profits swelled by salt
“Most of the salt eaten in the western world – in fact around 80 percent of it – comes from salt added to food from food manufacturers, and only around 20 percent comes from the salt cellar or the salt we use in cooking,” Cappuccio said.

“In terms of consumer freedom we have effectively no choice. At the end of the day, multinationals feed most of the world.”

Food manufacturers use salt to enhance the flavour of food that might otherwise be tasteless, to increase thirst and then seek to quench it with fizzy drinks, and also to boost profits from meat products, which are injected with a solution of salted water to plump them up and add weight.

In the worst cases, Cappuccio said, injected salt water makes up as much as 30 percent of the weight of a product like a chicken breast fillet.

“That 30 percent is pure profit [for the manufacturer],” he said. “We need to start a programme of reformulation of food items. But that’s the really tricky part, because that requires the food industry coming on board.”

But he pointed to some positive steps.

In the US, the New York City Health Department is leading a “National Salt Reduction Initiative”, bringing cities, states and health organisations together to work with food manufacturers and restaurants to try to reduce Americans’ salt intake by 20 percent over five years.

In Britain, it is partly due to public health campaigns and the efforts of the Food Standards Agency (FSA) to work with food makers to cut salt and give clearer labelling that intake levels have come down to 8.6 grams per day average from around 10 grams a day around 10 years ago.

“We know from scientific studies that if you reduce your salt intake by a little amount every day or every week or every month…then you can retrain your taste buds,” Cappuccio said.

“So we really can retrain people – whole populations – to enjoy food with less salt in it.”

The researchers found a new gene called New Delhi metallo-beta-lactamase, or NDM-1, in patients in Asia and in Britain. NDM-1 makes bacteria highly resistant to almost all antibiotics, including the most powerful class called carbapenems.

With international travel for healthcare on the rise, the scientists said they feared this new superbug could soon spread around the world.

In a study published in The Lancet Infectious Diseases journal, the researchers found that NDM-1 is becoming more common in Bangladesh, India, and Pakistan and is starting to be imported back to Britain in patients returning from these countries.

“India also provides cosmetic surgery for other Europeans and Americans, and it is likely NDM-1 will spread worldwide,” the scientists, led by Timothy Walsh from Britain’s Cardiff University, wrote in a report of their findings.

Multi drug-resistant bacteria are already a growing problem in hospitals across the world, marked by the rise of “superbug” infections like methicillin-resistant Staphyloccus aureus (MRSA).

Walsh and his international team collected bacteria samples from hospital patients in two places in India, Chennai and Haryana, and from patients referred to Britain’s national reference laboratory between 2007 and 2009.

They found 44 NDM-1-positive bacteria in Chennai, 26 in Haryana, 37 in Britain, and 73 in other sites in Bangladesh, India, and Pakistan.

Several of the British NDM-1 positive patients had recently travelled to India or Pakistan for hospital treatment, including cosmetic surgery, they said.

Most worryingly, NDM-1-producing bacteria are resistant to many antibiotics including carbapenems, the scientists said, a class of the drugs generally reserved for emergency use and to treat diseases caused by other multi-resistant bacteria such as MRSA and C-Difficile.

Experts commenting on Walsh’s findings said it was important to be alert to the new bug and start screening for it early.

“If this emerging public health threat is ignored, sooner or later the medical community could be confronted with carbapenem-resistant (bacteria) that cause common infections, resulting in treatment failures with substantial increases in healthcare costs,” Johann Pitout from the University of Calgary in Canada wrote in a commentary in the same journal.

They identified a piece of the virus that appears to be the same even among mutated strains, and found a way to make it into a vaccine.

Years of work lie ahead but if it works in people the way it worked in mice, the new vaccine might transform the way people are now immunised against influenza, the team at the Mount Sinai School of Medicine in New York reported.

“We now report progress toward the goal of an influenza virus vaccine which would protect against multiple strains,” Dr. Peter Palese, Dr. Adolfo Garcia-Sastre and colleagues report in a new journal mBio.

“Current influenza vaccines are effective against only a narrow range of influenza virus strains. It is for this reason that new vaccines must be generated and administered each year.”

Flu viruses mutate constantly and each year a cocktail of three flu vaccines is tweaked to try and hit the most common new mutations. Every few decades a new pandemic strain emerges – a year ago the new H1N1 swine flu strain started a pandemic and it has been added to the seasonal flu vaccine mix.

It takes months to make a new flu vaccine and governments and commercial drug companies struggled to get the new H1N1 vaccine out by last September. Having a universal flu vaccine could, in theory, prevent future pandemics and keep seasonal flu under better control.

Vulnerable neck

Palese’s team focused on an important piece of the flu virus called hemagglutinin. This mushroom-shaped structure helps the virus attach to the cells it infects and gives flu viruses the “H” in their names.

The “neck” of hemagglutinin does not mutate the way more visible bits of the virus do, and if there was an easy way to help the immune system to see it, this provides a good antigen – a target for a vaccine.

But the top, umbrella-shaped part of the hemagglutinin protein hides this vulnerable neck from the immune system. Palese’s team found a way to get to the neck, cut it out and make a vaccine out of it.

“A headless hemagglutinin molecule could form the basis for a broadly protective influenza virus vaccine,” the researchers wrote.

“This paper is more proof of concept,” Garcia-Sastre said in a telephone interview. “We don’t think we have yet the most optimal way to display the antigen.”

Tests in mice showed the vaccine protected them from otherwise lethal doses of multiple strains of influenza.

Garcia-Sastre’s team made a plasmid, a circular piece of DNA, for their vaccine but other ways to do it include a virus-like particle, used in other vaccines, or bits of DNA made by a baculovirus, he said. He said they are open to working with a drug company on this.

Flu infects up to 10 to 15 percent of the US population each year, more in a pandemic year, and kills an estimated 36,000.

Dozens of companies make influenza vaccines and bring in millions of dollars in revenues from them. The US, for instance, bought 162 million doses of H1N1 vaccine from five makers – Novartis, AstraZeneca unit MedImmune, Sanofi Aventis, GlaxoSmithKline and Australian vaccine maker CSL.

Raman, a business professor at nearby Harvard University, scoured the internet and spoke to dozens of scientists. They told him that if his daughter Nandita could hold on, a treatment being developed by Genzyme Corp might soon be available. In April, 2006, US regulators approved the drug, Myozyme, in time to save Nandita’s life.

“For motivating thousands of employees who collectively added years to our child’s life, and restored a smile to her face, we thank you,” Raman said, addressing Termeer before a packed auditorium at Babson College, which on April 7 inducted him into its Academy of Distinguished Entrepreneurs.

As the 64-year-old Termeer accepted his honor “with humility,” he was painfully aware that trouble was brewing. Federal regulators were about to sanction his company for manufacturing violations that led to shortages of two of its other life-saving drugs: Cerezyme, a treatment for Gaucher disease, and Fabrazyme, a treatment for Fabry disease.

And so it goes for Termeer, an urbane and charismatic Dutchman who has emerged as one of the biotechnology industry’s most celebrated – and controversial – figures. As a result of the latest setbacks, though, he is now in danger of losing control of the company he has spent the better part of three decades building.

Production problems
Patients with Gaucher, Fabry and Pompe disease are deficient in certain enzymes that break down fats or sugars in the body, leading to organ damage and, without treatment, death. Last year, a viral contamination forced the company to shut down its manufacturing plant in the Allston neighbourhood of Boston. To conserve supplies of Cerezyme and Fabrazyme, patients were forced to skip or take less of their medication. And though the plant is up and running again, Genzyme has repeatedly pushed back the time it will take to fully meet demand.

That has strained Termeer’s relationship with patient groups, and enraged Wall Street. Genzyme’s shares fell 26 percent in 2009 as the company scaled back earnings projections and yielded ground to competitors. For 16 years Genzyme monopolised the $1.2bn market for Gaucher disease. But in February, the US Food and Drug Administration approved Vpriv, a rival drug made by British drugmaker Shire Plc. It is expected to approve an experimental treatment made by Protalix BioTherapeutics Inc of Israel by the end of the year.

“As a large organisation, the challenges are different from those you face as an entrepreneur, and I’m sure you have read about the challenges we are facing,” Termeer told his Babson audience dryly.

Angry investors
The manufacturing crisis has also opened the door to activist investors. Carl Icahn, the billionaire known for taking control of underperforming companies and shaking up management, has nominated himself along with three other representatives to Genzyme’s board. Ralph Whitworth, another activist who runs the investment firm Relational Investors LLC, and who Genzyme recently appointed to its board, has called on the company to sell off parts of its business – such as its treatments for kidney disease – that are unrelated to its manufacture of drugs for rare diseases.

On June 16 investors will gather to vote on whether they consider Termeer the right person to steer the company out of its crisis.

Termeer insists he is. “We are on our way to overcoming the manufacturing challenges we have faced,” he said in an interview, “but still ahead is the need to regain the trust of our patients and physicians. I have known this community for many years. In fact, I developed this market from its inception. This isn’t the time to have someone else try to understand it.”

Some industry experts agree.

“Clearly there is a challenge to the company’s reputation, and clearly the products were not being made to the quality that is needed, and he needs to take ownership of that,” said Fred Hassan, the former chief executive of drugmaker Schering-Plough, who turned that company around after it suffered its own manufacturing crisis in 2002.

“But it is important that if investors ever consider changing him, whoever they replace him with must be immediately experienced in handling major manufacturing problems, and there are very few people like that,” he added. “Sometimes it is better to bring in the right crew and get on with it.”

Persuading investors to reinstate their trust in Termeer, however, won’t be easy.

“I think there is a good chance Icahn will get nominated to the board,” said Karen Andersen, an analyst at Morningstar. “A lot of investors are very unhappy at the way he has been leading the company.”

Icahn and his three other board nominees said in proxy filing in April they “believe that Genzyme’s inability to fully manufacture and supply certain of its products leads to the conclusion that the manufacturing system at Genzyme is ‘broken.'”

Key to his chances of holding on will be whether Termeer can convince investors that the problems are confined to manufacturing and can be “surgically” removed, as he insists, or whether investors believe they reflect a broader breakdown in leadership and operations.

Biotech pioneer
To chart how Genzyme and Termeer have reached this perilous position is to depict the arc of the industry itself. Genzyme is one of the oldest biotechnology companies in the world, and one of the last to remain independent.

It was founded in 1981 by Henry Blair, an enzymologist who had been collaborating with the National Institutes of Health (NIH) to develop a treatment for Gaucher disease using an enzyme known as glucocerebrosidase. The enzyme is found in human placentas, and Genzyme’s job was to collect the placentas, extract and purify the enzyme, and ensure enough quantity to support the clinical trials.

Termeer, a boyish-looking man who still retains his Dutch accent, joined the fledgling company in 1983 after a 10-year career at Baxter, a healthcare company known for producing successful young entrepreneurs.

From the start, Termeer wanted Genzyme to remain independent. To do that he believed it needed to be diversified and it needed to manufacture its own products, not just discover them. With the help of venture capital financing, Genzyme acquired two companies in England that produced raw materials for use in diagnostic testing and pharmaceuticals, and by the time the company went public in 1986, at $2.50 a share, it was generating revenue of nearly $10m.

“We didn’t want to become the research arm of a large pharmaceutical company,” he said. “The notion of building a business, rather than building a research company, became a very important characteristic of Genzyme.”

Independence had its cost. Genzyme was launched on the 15th floor of an old garment building in the red light district of Boston – known as the Combat Zone.

“I would park my car and walk to the office and before I got there I would be propositioned at least three times,” Termeer said. “It was an unusual kind of environment.”

Trials and tribulations
In 1984, the NIH ran its first trial of glucocerebrosidase in a Gaucher disease patient – Brian Berman, who was four. Berman’s belly had swollen to the size of a basketball and surgeons were about to take out his spleen.

“It was pushing all his other organs out of the way,” Termeer said.

The enzyme worked, and Berman’s belly shrank. The result had a powerful impact on Termeer, as well as on Berman’s family. To this day Termeer keeps a picture of Berman on the wall of his office in Cambridge, Massachusetts, and the two remain in touch.

“He is married, he has kids, and he still has his spleen,” Termeer says with pride.

But Genzyme’s scientific advisers were not convinced the company should try to develop a commercial product. It would require expensive clinical trials and, they argued – incorrectly as it turned out – gene therapy was around the corner.

Termeer was determined to press ahead. “I had so many detractors in those days, people who said you are out of your mind,” he said. “But I had seen this boy.”

To make matters worse, the NIH had conducted a new trial, of eight juvenile patients with Gaucher disease, and it failed – mainly because the patients had been bigger than Berman but had not received a greater dose of the drug. When the results were published, most researchers wrote it off.

Termeer, though, remained a believer, as did pioneering Gaucher disease researcher Dr Roscoe Brady and Brian Berman’s mother Robin, a physician. They decided to try to raise $10m to run a new clinical trial.

“We were in a tough situation,” Termeer said. “We had to prove that it worked.”

In June 1987, though more than eight months pregnant, Robin Berman joined Termeer and Brady as they criss-crossed the country in search of funding. It was an arduous task. No-one would give them a cent. The trial results, after all, appeared to speak for themselves.

Then, one day, as Berman was speaking to brokers and wealthy individuals in Albany, New York, her water broke.

“She turned to me for help,” Termeer said. “What was I to do? I’m an economist!”

The episode seemed to jolt the audience.

“Suddenly they got it,” Termeer said. “They called their friends and we raised the money.”

Three weeks later the stock market crashed.

“If we had been any later it would have been a very different story as all financing was then off the table.”

“Crazy dreaming”
The US Food and Drug Administration agreed to let Genzyme conduct a trial of 12 patients – a bold move since it was the height of the AIDS crisis and the agency was concerned about pooling placental fluid.

Patients came from around the world. One flew in twice a month from Germany, courtesy of the German government. Another family moved to Washington DC from South Africa. Two patients in the trial nearly died. And the leg-work involved in producing the enzyme was grueling.

“Every time we ran out of the enzyme we would go around with a little car to all the hospitals in New England and get the placentas,” Termeer said. “Then we would carry them up to the 15th floor where we would fractionate and purify them.”

The purification process took place in two tiny centrifuges. When they were turned on, the entire building, and all the garment workers on the lower floors, shook.

“They tolerated it. They knew it was for a good cause,” Termeer said.

In the end, the drug worked in all the patients, and in 1991 the FDA approved the product, which became known as Ceredase.

“We had a reunion 20 years later,” Termeer said. “We sat together in a hotel here. A lot of crying went on.”

The collection of placentas to produce Ceredase for a larger number of patients became an enormous undertaking. But it happened that Pasteur Merieux, a company in Lyon, France, was using placental blood to produce immunoglobulins and albumin, a substance used to expand blood supplies for use in wars or accidents.

“They would process these placentas in beautiful French wine presses,” Termeer said. Then they would hand over the remaining tissue to Genzyme, which would extract the enzyme. Ultimately, around 30 percent of all placentas from births in the US, and around 70 percent of placentas from Europe, found their way to that plant. Eventually, Genzyme created a genetically-engineered version of Ceredase using Chinese hamster ovary cells. That drug, Cerezyme, was approved by the FDA in 1994, and Genzyme opened its plant in Allston – the plant at the centre of today’s troubles – in 1996.

“When you look at the history of Ceredase, how Henri had to convince the people to do the trial, how it failed, how he went back, it was almost crazy dreaming,” said John Crowley, the chief executive of Amicus Therapeutics Inc and co-founder of Novazyme, a company that had also been developing a treatment for Pompe disease and that Genzyme acquired in 2001. “This was the kind of risk-taking innovation and dreaming that made biotech great. Henri absolutely broke the mold and the paradigm.”

Polarising figure
Termeer is hoping that his history of achievement will be enough to persuade investors to give him the chance to steer Genzyme through its current crisis. But he has his work cut out for him.

“It’s going to be a very difficult thing for him to get a second shot and retain the authority to do the things he wants to do,” said Oliver Pursche, executive vice president at Gary Goldberg Financial Services.

Termeer is in many ways, a polarising figure, having transformed himself from a scrappy entrepreneur into a leading figure in Boston’s financial, scientific and artistic community. Besides running Genzyme, he sits on the boards of the Massachusetts General Hospital and Massachusetts Institute of Technology; is chairman of the Federal Reserve Bank of Boston’s board of directors and is a member of Massachusetts Governor Deval Patrick’s Council of Economic Advisors.

“Henri is the ultimate renaissance man, the Thomas Jefferson of Boston,” said Jack Meyer, a friend who formerly managed Harvard University’s endowment fund and is now chairman of the Boston ballet’s board of trustees. “He thinks deeply, he thinks broadly, he sees all of life and is involved in all.”

But to hear others tell it, there is a darker, more calculating side to Termeer.

In December, 2000, Genzyme acquired Biomatrix Inc, which had developed an injectable treatment for osteoarthritis called Synvisc. Genzyme combined Biomatrix with two of its separately traded units, Genzyme Surgical Products and Genzyme Tissue Repair, to form a new company, called Genzyme Biosurgery. Biosurgery traded independently as a tracking stock.

Tracking stocks are equities tied to the performance of a particular segment of a company’s business and can be a way to unlock the value of a high growth unit without spinning it off to shareholders. They were popular during the dot.com era of the 1990s but fell out of favor after the Enron accounting scandal in 2001 cast a pall over complex financing vehicles.

Lawsuit challenged buyback
In May 2003, Genzyme eliminated its tracking stock structure. Under its articles of organisation Genzyme could force Biosurgery shareholders to sell their shares back at 130 percent of fair market value. Genzyme acquired Biosurgery shares for $1.77 each.

To Biosurgery shareholders, the payment amounted to highway robbery. Rory Riggs, the former president of Biomatrix, and John Lewis, a partner at investment firm Gardner Lewis Asset Management and Biosurgery shareholder, filed a class action lawsuit against Genzyme and its executives, including Termeer.

The lawsuit, amended in 2005, charged Genzyme’s executives with deliberately driving down the value of Biosurgery’s stock in order to buy it back at a price beneficial to Genzyme’s shareholders but grossly unfair to Biosurgery shareholders.

“Henri intentionally, with ill will, defrauded his own shareholders to whom he had a fiduciary duty, to make himself more wealthy,” Lewis said. “In my opinion he belongs not in the jail but underneath the jail.”

According to the suit, Genzyme’s own internal valuations reflected their belief that the true value of Biosurgery’s shares ranged from $12.75 to more than $50 a share. It alleged that by March 1, 2002, Termeer had already decided to eliminate Biosurgery’s stock. A memorandum from that day’s meeting obtained in discovery states that “we are working toward reabsorbing GZBX,” Biosurgery’s stock symbol.

Between January and July, 2002, Genzyme’s shares fell more than 70 percent amid earnings downgrades and suspicions that the company had kept inventory levels of its kidney disease drug Renagel high in order to artificially boost sales – a practice known as channel-stuffing.

The decline meant a repurchase of Biosurgery could be dilutive to Genzyme’s earnings.

“Against this backdrop, on May 24, 2002, Termeer met with one of his senior colleagues to prepare for the May 2002 Board meeting, to be held five days later,” the suit states. “A remarkable note from that May 24 meeting – ‘letting GZBX success occur – compare pluses and minuses’ – suggests that he decided to solve this problem by turning to an unusual method for a chairman and chief executive of a public company: he decided to work to limit Biosurgery’s apparent success to enable its tracking stock to be repurchased on favourable terms for Genzyme’s shareholders.”

In 2007, shortly before the case was due to go to trial, Genzyme agreed to settle for $64m – or twice the amount it had originally paid Biosurgery shareholders.

To the shareholders, the settlement was an implied admission of guilt. But Termeer says he settled the case to avoid the risk of a trial, and said $64m was a small amount – an indication that the case was “not that big.”

“There was no interest on any of our parts to be anything other than fair.”

Still, Genzyme has never been considered an especially transparent company. Investors have criticised it over the years for its opaque compensation structure, accounting practices and excessively passive board.

Cognizant of that distrust, Termeer has moved to more closely align senior executive pay with performance, alter the company’s accounting practices to bring them in line with its peers, and introduce new people onto the board.

He recently scaled back his own compensation. In 2009, his total package declined 25 percent to $9.5m from $12.7m. Even so, he still received an increase in salary of 8.7 percent and kept the car and driver that ferry him back and forth from his $4m ocean-front home in Marblehead, on Boston’s north shore, at a cost of $81,386.

Termeer concedes there is a price to be paid for a CEO to be at the helm too long.

“I need to move on, both for myself and the health of the company,” he said. “But I want to get us through this problem and start to prepare the company for its next phase in 2011.”

Most people wouldn’t naturally associate mining with nano- or green technology, would they? But at Imerys, the world’s leading producer of industrial minerals, that’s exactly what they do, and they’ve dedicated a significant proportion of their R&D effort to both of them.

Nanotechnology is a term that embraces such an enormous range of subjects that it can be hard to understand what it actually means. In material science, however, it’s more specific; it’s about the use of nanometre-sized particles of often quite ordinary substances to obtain new and useful properties that don’t exist at other scales. The earliest examples are becoming well known – suncreams, self-cleaning glass, scratch-resistant coatings and carbon nanotube reinforced composites are typical. All of these use synthetic nanoparticles made by cooking up various chemicals, often in the gas phase, at very low throughput and using large quantities of energy. So, not surprisingly, they come with a hefty price tag.

Natural industrial minerals, by contrast, are found everywhere – in ceramics, beer and wine production, cosmetics, paints, paper, plastics and rubbers – where they reinforce, filter, toughen, stiffen and above all whiten the materials of our daily lives. The need for whiteness specifically requires particles of micrometre rather than nanometre sizes, but nevertheless many mineral products have always contained a significant proportion of nano and near-nano dimensioned particles. Over the last few years, Imerys has been busy extracting and processing these for a range of new properties and applications. Examples include a toughening agent for clear coatings, where nano size is needed to achieve the clarity and transparency required for the most demanding applications, and microcapsules made from a polymer/mineral nanocomposite which protect their precious cargo of  active ingredients from their surroundings and release them exactly when and where they are needed. And the great thing about using particles extracted this way is that we know they’ve been a safe, tried and tested part of everyday materials for centuries, so there’s no need to fear any unseen health risks from their use.

So how, you might ask, can an industry that extracts minerals by the millions of tonnes be called green? Take a look around you, and consider the fact that the things you see are made up from raw materials, and if these can’t be grown they have to be dug out of the ground. So it’s not whether we mine materials, but what they are, how we do it and how we use them that counts. An example: the conventional role of minerals in petroleum-based plastics is to reinforce and stiffen them, reducing the amount of polymer needed for a given task, and achieving the goals of lower cost and sometimes even lower weight. Do the sums, and you find that, more often than not, this reduces the carbon footprint of the product as well.

It doesn’t stop there; Imerys is currently working with UK partners on minerals that will raise the performance of the new generation of bioplastics to the point where they can take over from the conventional ones made from oil. Add in the fact that the minerals simplify and markedly speed up the moulding and processing steps, and the potential is clear.

Finally, at the end of a product lifecycle the mineral components are relatively easy to recover, as they will survive combustion and other high temperature processes needed to purify mixed wastes. Imerys has already developed specialist materials made from sources as diverse as broken glass bottles and the mountains of sludge created by paper recycling. So take a new look at natural minerals, and realise the potential that Imerys has already begun to unlock.

Further information: www.imerys.com

Ablynx specialises in nanobodies – touted as the next generation in antibody treatment – which are developed from the antibodies in llamas. They have the potential to enable drugs to get to diseases that are too small for traditional antibodies to reach.

One of its lead drugs, being developed in partnership with US drugs giant Pfizer, which inherited it when it took over Wyeth last year, is currently in Phase II trials and could become its first commercialised product.

“The earliest we think it could be on the market is 2013, that’s a tangible distance away,” Chief Executive Edwin Moses told reporters.

Pfizer is hoping it will be able to use the new nanobody drug to replace its arthritis medicine Enbrel – which made almost $1bn in the third quarter of 2008 – Moses said.

The company also has partnerships with Merck, Boehringer Ingelheim and Novartis.

In a twist of nature, llamas have evolved to produce extra small antibodies, which are in turn used to make nanobodies. They are stable enough to be inhaled or inserted under the skin, setting Ablynx’ technology apart from rivals like GlaxoSmithKline’s Domantis, Moses said.

In tests on animals, nanobodies have shown they could replace aspirin and even treat Alzheimer’s disease, and they are currently in mid-size human trials for arthritis and thrombosis.

They also cost about a third of the price of developing traditional antibodies, Moses said.

“We take two or three llamas, give them an injection and go away on holiday [and create] what might have taken 20 medical chemists a year to come up with,” said Moses.

Many of us turn to personal recommendations when deciding to make a purchase, but the sheer volume of online customer feedback now available can be just as daunting.

Leading online retailers – notably Amazon – were quick to develop personal recommendation software, analysing a customer’s buying patterns to suggest other products that they might enjoy.

A team of European researchers are now taking that approach a step further.

Alexander Voss, a researcher at Microsoft’s European Innovation Centre in Aachen, Germany, is coordinating seven companies and universities that are developing advanced methods, models and algorithms to bring personalised recommendations to everything from web content and interactive TV channel guides to e-commerce.

Their algorithms, developed in the EU-funded MyMedia project, combine two sources of data. “Stable information” is derived from user-created profiles – covering details such as age, residence, likes and dislikes – and the star∞ratings they give to past purchases, such as films they have enjoyed.

“Unstable information” reflects factors such as context, the user’s mood and tastes, and what types of music they tend to listen to.

Most personalised recommendation technology looks at unstable information as a black and white issue: if a user watched one video they must want to see more like it.

But the MyMedia researchers are adding a third and very important variable when it comes to finding what people really want. “We’re not just looking at choices in terms of ‘yes’ or ‘no’, but also ‘maybe’,” Voss explains.

“Just because someone didn’t watch a certain video doesn’t mean they wouldn’t want to, they simply might not have had the time or felt like it at that moment.

“Instead of excluding it, we add it to a relative ranking of recommended content that changes over time as the system builds up a better idea of the user’s interests.”

The system is unique in another way too: it allows content providers to fine-tune recommendation parameters to see how the changes affect users’ responses. “There is no other recommender system that can do that,” Voss says.

The technology is being tested by e-commerce company Microgénesis, telecoms company BT and the BBC. If it catches on, we could soon have more time to spend enjoying our choices, rather than worrying about what choice to make.

Complete with beanbags and coffee served in steel tumblers, an office in Mumbai is helping change the perception that India is no place for top-end research and development.

Staffed with about 60 full-time researchers, many of them Indians with PhDs from top universities in the United States, the centre is at the cutting edge of Microsoft’s R&D. It covers seven areas of research including mobility and cryptography.

Its success, including developing a popular tool for Microsoft’s new search engine Bing, underscores the potential of R&D in India at a time when cost-conscious firms are keen to offshore to save money by using talented researchers abroad.

Showing off the Bing tool which enables searches for locations with incomplete or even incorrect addresses, B. Ashok, a director of a research unit at the centre, said the innovation would never have taken root if the R&D had been done in the United States.

“It was completely inspired by the Indian environment, but is applicable worldwide,” he said.

Structural problems
While India might seem like a natural location to expand offshoring into R&D, it is hampered by some serious structural problems that range from not enough home grown researchers to a lack of government support.

India produces about 300,000 computer science graduates a year. Yet it produces only about 100 computer science PhDs, a small fraction of the 1,500-2,000 that get awarded in the United States, or China, every year.

“Students here are not exposed to research from an early age, faculties are not exposed to research and there’s no career path for innovation because there’s a lot of pressure to get a ‘real’ job,” said Vidya Natampally, head of strategy at the Microsoft India Research Centre.

With few government incentives and an education system that emphasises rote learning, India lacks the kind of environment found in say, Silicon Valley, where universities, venture capitalists and startups encourage innovation.

“China has a policy in place for R&D; we don’t,” Natampally said, adding that India could move up the value chain faster if even a small percentage of its engineering graduates went into research.

The small numbers of PhDs and the lack of government incentives for India’s fledgling R&D sector are blunting the country’s edge, analysts warn.

Competition
Rival China has already pulled ahead with more than 1,100 R&D centres compared to less than 800 in India, despite lingering concerns about rule of law and intellectual property rights.

Aside from providing funding to encourage students to complete their PhDs, China also offers fiscal incentives such as tax breaks for R&D centres and special economic zones provide infrastructure for hi-tech and R&D industries. India is also losing out in the patent stakes. In 2006-2007, just 7,000 patents were granted in this country of 1.1 billion people, compared to nearly 160,000 in the United States.

“We’re nowhere near the US or even Israel when it comes to innovations,” said Praveen Bhadada at consultancy Zinnov, which estimates the R&D sector in India is worth about $9.2 billion.

“Our costs are low and our talent pool is ahead of China, Russia and Ukraine, but China gives specific incentives, and produces way more PhDs than we do.”

India is cheaper than China for R&D, those in the industry in Bangalore said. But salaries in India have been rising by about 15 percent every year and may soon reach parity with China. R&D centre costs in Shanghai are currently just 10-15 percent higher than in India.

Beyond coding
Microsoft and other firms have been working around the government’s indifference. Cisco, IBM, Intel, Nokia, Ericsson and Suzuki Motor have all gone beyond low-end coding and tweaking products for the local market, with hefty investments and recruitment.

Their success shows India’s potential if the government starts supporting such ventures and building high-tech parks and incubators.

“If Paris asks for some work, it’s not because they think it’s cheaper but because they want inputs from India,” said Jean Philippe, chief designer of the Renault India Studio, which competes with the French carmakers’ five other global studios.

Texas Instruments and San Jose-based Cadence Design were among the first to set up R&D in India in the mid-80s, drawn by the legions of English-speaking software engineers who could be hired at about 20 percent of the cost of engineers in the United States.

The opening of the economy in the early 90’s and the establishment of the software services industry drew more foreign firms looking to cut costs and tap emerging markets.

“From when a few companies offshored non-critical design work, we have seen India emerge as a preferred destination for design and development of chip, board and embedded software,” said Jaswinder Ahuja, managing director of Cadence India.

Firms first focused on the ‘D’ in R&D, but research has grown in importance in recent years, and many of the facilities in India are now the largest outside their home base.

Half of Cisco’s core R&D work, including innovations in WiMAX and optical networks, and about 40 percent of SAP’s ideas for processes and product development come from India.

“The Indian units are more tuned to the needs of customers in emerging markets. Besides, Bangalore is only a 5-hour flight away from three strategic regions: Southeast Asia, east Asia and the Middle East,” said Aravind Sitaraman, vice president at Cisco.

IBM’s India Research Labs do a “fair share of patenting”, helping swell the parent’s record numbers every year, said director Guruduth Banavar in Bangalore.

Its new $100 million-mobile communications research, Mobile Web, is the first time a big project has been driven from outside the United States, he said.

“For a research lab it’s the best environment to be in: you can see the problems and the opportunities,” said Banavar, who was previously at IBM’s lab in Boston and has, like several of his peers, returned to India to oversee operations here.