Pfizer’s Rare Heart Disease Drug Succeeds in Late-stage Study

Pfizer Inc said on Thursday its drug tafamidis, for a rare and fatal disease associated with progressive heart failure, met the main goal in a late-stage study.

The company’s clinical study investigated the efficacy, safety and tolerability of an oral dose of tafamidis capsules compared with a placebo in 441 patients.

Pfizer said tafamidis showed statistically significant reduction in deaths and frequency of cardiovascular-related hospitalizations compared with a placebo at 30 months. The data also showed that tafamidis was generally well tolerated by the enrolled patients.

Tafamidis was being tested for the treatment of transthyretin cardiomyopathy, a condition that results from deposits of transthyretin protein in the heart, which leads to eventual heart failure.

The U.S. Food and Drug Administration granted tafamidis a ‘fast track’ designation in June last year. The designation aims to facilitate the development and expedite the review process for certain drugs and vaccines for serious conditions.

Currently, there are no approved medications in the United States for the treatment of transthyretin cardiomyopathy.

Pfizer’s Rare Heart Disease Drug Succeeds in Late-stage Study

Pfizer Inc said on Thursday its drug tafamidis, for a rare and fatal disease associated with progressive heart failure, met the main goal in a late-stage study.

The company’s clinical study investigated the efficacy, safety and tolerability of an oral dose of tafamidis capsules compared with a placebo in 441 patients.

Pfizer said tafamidis showed statistically significant reduction in deaths and frequency of cardiovascular-related hospitalizations compared with a placebo at 30 months. The data also showed that tafamidis was generally well tolerated by the enrolled patients.

Tafamidis was being tested for the treatment of transthyretin cardiomyopathy, a condition that results from deposits of transthyretin protein in the heart, which leads to eventual heart failure.

The U.S. Food and Drug Administration granted tafamidis a ‘fast track’ designation in June last year. The designation aims to facilitate the development and expedite the review process for certain drugs and vaccines for serious conditions.

Currently, there are no approved medications in the United States for the treatment of transthyretin cardiomyopathy.

One of World’s Biggest Drug Companies Just Abandoned Alzheimer’s And Parkinson’s Research

Pfizer, the world’s third largest drug maker, has announced it is ending research to discover new medications for Alzheimer’s and Parkinson’s disease.

The move, which will eliminate hundreds of research positions across the pharmaceutical giant’s roster, casts an even darker shadow outside the company – dashing the hopes of millions affected by neurological disorders, whose dreams of finding a treatment just got that much more desperate.

“As a result of a recent comprehensive review, we have made the decision to end our neuroscience discovery and early development efforts and re-allocate [spending] to those areas where we have strong scientific leadership and that will allow us to provide the greatest impact for patients,” the company said in a statement to NPR.

Job reductions primarily in Massachusetts and Connecticut are expected to occur across the next several months, although the company is continuing research into rare neurological diseases, and plans to launch a venture fund committed to neuroscience.

To many, though, those gestures won’t replace the loss of some 300 neuroscientists and associated staff in an organisation that bills itself as “the world’s largest research-based pharmaceutical company”.

“Any decision impacting colleagues is difficult,” the company’s statement reads.

“[H]owever, we believe this will best position the company to bring meaningful new therapies to market, and will bring the most value for shareholders and patients.”

Of course, value for shareholders is one thing; but for patients, especially those affected by neurological diseases (and their families), it’s quite another, as critics of Pfizer’s new direction are eager to make clear.

“[W]ith no new drug for dementia in the last 15 years, this will come as a heavy blow to the estimated 46.8 million people currently living with the condition across the globe,” says the head of research at the UK’s Alzheimer’s Society, James Pickett.

“Every three seconds someone in the world develops dementia and, with this number set to rise, there has never been a more important time for such life-saving research.”

That’s especially so since the best, mostly ineffective medications we have for conditions like Alzheimer’s are in fact the products of research from decades ago.

While there are strong hopes they can be improved upon – and treatments for Parkinson’s and other neurological conditions too – until more research is done, a hoped-for, effective replacement won’t materialise.

“The current medication for Alzheimer’s disease is approved, essentially, because it’s better than nothing. There’s nothing else at the moment,” neuroscientist Joseph Jebelli told NPR last week.

“These drugs were pioneered in the ’70s and ’80s and they treat the symptoms, as opposed to the underlying biology.”

 Of course, one company announcing the closure of one wing of medical research doesn’t signal the end of other scientists working in that field – but in light of Pfizer’s dismaying decision, some commentators are wondering what this means for the rest of the big pharma landscape in terms of neuroscience research.

“It’s really alarming to see such a large pharmaceutical company deciding to abandon research into the brain and central nervous system,” chief scientific officer at the Parkinson’s Foundation, James Beck, told the Los Angeles Times.

“[H]aving Pfizer exit does not augur well for what other companies are likely to do.”

That’s especially so since Pfizer’s decision follows a series of clinical failures by other companies pursuing Alzheimer’s research – developments that can be extremely costly for the companies invested in the trials.

We’ll have to wait and see what happens here – and hope the companies committing to this research keep focussed on what’s really at stake here.

“[N]euroscience research is high risk, in that failure for pharmaceutical companies comes at a high price,”Alzheimer’s Research’s director of policy, Matthew Norton, told The Times.

“[But] the potential benefits of success to the millions of people around the world living with dementia are too great to ignore.”

The FDA just shot down a new rheumatoid arthritis drug.

The FDA just rejected a new daily pill to treat rheumatoid arthritis.

rheumatoid arthritis

Pharmaceutical companies Lilly and Incyte said on Friday that their drug, baricitinib, had been issued a complete response letter , which explains why the drug didn’t get approval.

In its letter, the FDA told Lilly and Incyte that it wanted more data on what the right dose for the drug is. The FDA also wants more data about potential safety issues.

The FDA had previously pushed back its review date of baricitinib by three months. Even so, analysts largely expected the FDA to approve baricitinib, especially after the European Commission approved the drug in February. If approved would have been a competitor to Pfizer’s Xeljanz.

“We are disappointed with this action. We remain confident in the benefit/risk of baricitinib as a new treatment option for adults with moderate-to-severe RA,” Christi Shaw , Lilly Bio-Medicines president said in a news release . The companies plan to resubmit the drug to the FDA.

Rheumatoid arthritis is a common, chronic inflammatory condition that affects the joints. There are a number of ways to treat the disease, such as the chemotherapy drug methotrexate.

Soure: BMJ

Pfizer Vice President Blows The Whistle & Tells The Truth About The Pharmaceutical Industry

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Below is a clip taken from the “One More Girl” documentary, a film regarding the Gardasil vaccine, which was designed to prevent Human Papillomavirus. In it, Dr. Peter Rost, MD, a former vice president of one of the largest pharmaceutical companies in the world (Pfizer), shares the truth about the ties between the medical and pharmaceutical industry.

Rost is a former vice president of Pfizer, and a whistleblower of the entire pharmaceutical industry in general. He is the author of “The Whistleblower, Confessions of a Healthcare Hitman.” Considering his work experience, it would be an understatement to say that he is an insider expert on big pharma marketing.

Below are a couple of quotes from both a former and a current editor-in-chief of the two largest, and what are considered to be the most credible, medical journals in the world. It’s only fitting to include them into the article as they are directly related to what Dr. Rost hints at in the video.

“It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of the New England Journal of Medicine.”  – Dr. Marcia Angell, a physician and longtime editor-in-chief of the New England Medical Journal (NEMJ) (source)

“The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.”  – Dr. Richard Horton, the current editor-in-chief of the Lancet – considered to be one of the most well respected peer-reviewed medical journals in the world. (source)

It’s Time To Re-Think Current Medical Research & See The Bigger Picture

In 2005 Dr. John P.A. Ioannidis, currently a professor in disease prevention at Stanford University, published the most widely accessed article in the history of the Public Library of Science (PLoS) entitled Why Most Published Research Findings Are False. In the report he states:

“There is increasing concern that most current published research findings are false.”

We now have a large amount of evidence, and statements from experts that come directly from the field, which paint a very concerning picture. The science used to educate doctors and develop medicine is flawed. We are only ever exposed to studies that have been sponsored by big pharmaceutical companies, but these studies are not designed to take the long view. They are not designed to detect problems that can occur years or even decades after a treatment, or examine the risks of taking a drug for long periods of time. Nobody ever seems to mention or acknowledge the many studies which clearly show significant risk associated with many of the products that pharmaceutical companies are manufacturing to help fight disease.

What is even more concerning is the general population’s lack of awareness when it comes to these facts. This issue is definitely not going to be addressed in the mainstream news, and despite plenty of evidence to support it, some people will refuse to even look at or acknowledge that it exists. This is a big problem, our world is changing and we must keep an open mind and be open to new possibilities regarding the nature of our world. It’s 2015, and as we keep moving forward there will be more information coming out that challenges the deeply held, engrained belief systems of many. It’s okay to look at information that goes against what you believe, in fact, it’s needed if we are going to move forward and create a better world for ourselves.

You would think the statements above the video, from longtime editors of such major, peer-reviewed scientific journals (apparently, the best in the world) would at least get some mainstream attention.

When Dr. Rost was still working for Pfizer he had a couple of appearances in the mainstream media. Hereis an example of him speaking with the Wall Street Journal almost 10 years ago, before he blew the whistle.

This is why alternative media is important, especially in a time where more and more people are waking up to what is really happening on our planet.

It’s time to examine the research that’s being conducted all over the world, from experts (scientists) at various institutions, that is not sponsored by these giant, multinational “health” corporations – the independent literature. Brilliant work is being published regarding various drugs, cures, treatments, vaccines, and more.

watch the video. URL:

Pfizer ‘Hid Link’ Between Anti-Depressants and Birth Defects Alex Jones’ Infowars: There’s a war on for your mind!

Pharmaceutical mammoth Pfizer faces more than 1,000 lawsuits from victims who say that the company knew about the relationship between birth defects and their #1 best-selling anti-depressant. A claim that Pfizer has, of course, battled against.

Report: Pfizer ‘Hid Link’ Between Anti-Depressants and Birth Defects

Now, however, new reports have surfaced that Pfizer’s own scientific advisers were warning of the deadly link for more than a year. Something that my team told you in 2012 was already going on. According to Bloomberg:

“A Pfizer Inc. report shows a scientist warned executives last year about a potential link between the anti-depressant drug Zoloft and birth defects and recommended changes to the medication’s safety warning.
The document from a Pfizer drug-safety official might complicate the company’s efforts to fend off lawsuits brought by parents of children with malformed hearts. Pfizer has consistently rejected suggestions Zoloft caused newborn abnormalities and said Monday the document was taken out of context by lawyers suing the company.”
In other words, Pfizer likely employed a popular Big Pharma tactic: ignore any science that reveals serious side effects, and instead choose to pay some relatively meager fines for the damages. After all, paying a few million (or billion) in fines is often nothing compared to the profits from drugs like Zoloft, which rakes in around $2.9 billion per year alone.

After all, Pfizer has a familiar history with government fines. It was in 2009 when the corporation paid one of the largest health care fraud settlements of all time, shelling out $2.3 billion for “the intent to defraud or mislead” consumers with their painkiller Bextra. Again, a fine that is less than the sales of Zoloft for a single year.

As we read further down into the Bloomberg report, yet again it seems that research indicating serious side effects was simply ignored:

“Pfizer researchers also acknowledged in a 1998 report, which has been introduced into evidence in the Philadelphia trial, they’d found more than a dozen side-effect reports about babies’ birth defects for which their mothers’ Zoloft use couldn’t be ruled out as a cause.”
Sadly, this is nothing new for the mega pharmaceutical conglomerate. Eli Lilly & Co., the manufacturers of Prozac, did their best to hide the link between Prozac and increased risk of suicide for a number of years. Ultimately, it took a Harvard psychiatrist to proclaim that Americans were being treated like ‘guinea pigs’ by Eli Lilly & Co.’s Prozac for real public interest.

Will Pfizer end up paying a couple billion or less in fines for leading to an unknown number of life-threatening birth defects? It is the most likely outcome, for which the company is quite thankful. As long as they can write off the settlement loss and continue to take in the yearly profits, the company will get over it quickly.

Developer of Viagra is knighted

The scientist who was responsible for developing Viagra has been knighted.

Dr Simon Campbell oversaw the development of the erectile dysfunction drug for Pfizer. Since it went on sale in 1998 more than a billion of the pills have been sold.

He also helped develop Cardura, which is used to treat high blood pressure and angina, and Norvasc, for high blood pressure and prostate enlargement, some of the world’s bestselling prescription drugs.

He has authored more than 110 patents and publications.

Campbell, 73, retired from Pfizer in 1998 and was highly critical when the American pharmaceuticals company announced it was to close its giant research centre at Sandwich, Kent, in 2011, saying it would compromise the UK’s status as a centre of excellence for pharmaceutical research.

During his tenure as President of The Royal Society of Chemistry he campaigned for more funding and an improved image for chemistry.

He was made a CBE for services to science in 2006.

Lipitor Without a Rx? Pfizer Pushes Ahead With OTC Plans.

Pfizer, the maker of Lipitor, is pushing forward with efforts to sell its drug to patients without a doctor’s prescription, according to the Wall Street Journal.

The company recently launched a 1200-patient study to investigate whether patients could successfully take over-the-counter (OTC)atorvastatin to lower their LDL-cholesterol levels. Patients in the trial, which is currently recruiting at 35 US pharmacies, would get their own blood tests and would make decisions based on those results.

A positive study would determine whether Pfizer will file for regulatory approval of its OTC medication, according to the Journal.

Simvastatin has been available OTC at the 10-mg dose in the UK for nearly 10 years. Merck has gone before the US Food and Drug Administration three times since 2000, but the agency has turned away its drug, lovastatin (Mevacor) 20 mg, each and every time. Merck sought approval of OTC lovastatin in moderate-risk patients and aimed to market its drug to the “motivated health-conscious consumer.”

Like Merck, Pfizer says an OTC Lipitor would close the gap for people at risk of cardiovascular disease but who are not currently taking the lipid-lowering therapy.

Dr Neil Stone (Northwestern University Feinberg School of Medicine, Chicago, IL), the chair of the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the treatment of cholesterol, told the Journal the new guidelines do not support OTC use of statins. In fact, the new guidelines don’t recommend treating to LDL targets any longer but instead recommend a moderate- or high-potency statin based on patient’s 10-year risk of cardiovascular disease.

Given that Pfizer is investigating the feasibility of just a 10-mg dose of Lipitor, undertreatment is a concern. “There’s a chance that a lot of people would take less than needed,” Dr Steven Nissen (Cleveland Clinic, OH) told the Journal.

At one stage, Lipitor was the world’s biggest-selling drug, with sales peaking at $13 billion in 2006, but since the patent expired sales have declined to $2.3 billion in 2012, reports the Journal.

Could arthritis drug combat Alzheimer’s?

Alzheimer’s affects 35 million people worldwide and billions have been spent on research – to little avail. But an unconventional approach based on a 30-year-old evolutionary theory might provide a way forward
alzheimers graphic View larger picture

At the beginning of next year, Clive Holmes will attempt to do something remarkable. But you’d never guess it from meeting this mild-mannered psychiatrist with a hint of a Midlands accent. In fact, you could be sitting in his office in the Memory Assessment and Research Centre at Southampton University and be unaware that he was up to anything out of the ordinary – save for a small whiteboard behind his desk, on which he’s drawn a few amorphous blobs and squiggles. These, he’ll assure you, are components of the immune system.

As a psychiatrist, he’s had little formal training in immunology, but has spent much of his time of late trying to figure how immune cells in the body communicate with others in the brain. These signals into the brain, he thinks, accelerate the speed at which neurons – nerve cells in the brain – are killed in late-stage Alzheimer’s disease and at the beginning of next year he hopes to test the idea that blocking these signals can stop or slow down disease progression.

If he shows any dent on disease progression, he would be the first to do so. Despite the billions of pounds pumped into finding a cure over the last 30 years, there are currently no treatments or prevention strategies.

“Drug development has been largely focused on amyloid beta,” says Holmes, referring to the protein deposits that are characteristically seen in the brains of people with Alzheimer’s and are thought to be toxic to neurons, “but we’re seeing that even if you remove amyloid, it seems to make no difference to disease progression.”

He mentions two huge recent failures in drugs that remove amyloid. The plug has been pulled on bapineuzumab by its developers Johnson & Johnson and Pfizer after trials showed its inability to halt disease progression; and the wheels seem to be coming off Eli Lilly’s drug solanezumab after similarly disappointing results.

Other drugs in the experimental pipeline are a long way off. Few make the jump from efficacy in animals to efficacy in people. Fewer still prove safe enough to be used widely.

Holmes’s theory, if true, would have none of these problems. He’s been testing etanercept, a drug widely used for rheumatoid arthritis. It blocks the production of TNF-alpha, one of the signalling molecules, or cytokines, used by immune cells to communicate with each other. In the next few months, he expects the results of a pilot trial in people with Alzheimer’s. If they are positive, he’ll test the strategy in people with only the mildest early forms of the disease.

“If we can show that this approach works,” says Holmes, leaning forward in his chair, “then since we already know a hell of a lot about the pharmacology of these drugs, I’m naive enough to think that they could be made available for people with the disease or in the early stages of the disease and we can move very quickly into clinical application.”

It seems too good to be true. Why, then, has the multibillion-pound drug industry not at least tested this theory? There are roughly 35 million people in the world with this devastating, memory-robbing disease, and with an increasingly ageing population, this number is expected to rise to 115 million by 2050. It’s not as if there is no financial incentive.

The answer might be because the idea that Holmes and his colleagues are testing took an unconventional route to get to this point. It started life as an evolutionary theory about something few people have even considered – why we feel ill when we are unwell. The year was 1980. Benjamin Hart, a vet and behavioural scientist at the University of California, Davis had been grappling with how animals in the wild do so well without veterinary interventions such as immunisations or antibiotics. He’d attended a lecture on the benefits of fever and how it suppresses bacterial growth. But fever is an energy-consuming process; the body has to spend 13% more energy for every 1°C rise in body temperature.

“So I started thinking about how animals act when they’re sick,” says Hart. “They get depressed, they lose their appetite. But if fever is so important, what they need is more food to fuel the fever. It didn’t stack up.”

After a few years of mulling this over, Hart published a paper on what he termed “sickness behaviour” in 1985. Lethargy, depression and loss of appetite were not, as people thought, a consequence of infection, but a programmed, normal response to infection that conferred a clear survival advantage in the wild. If an animal moves around less when ill it is less likely to pick up another infection; if it eats or drinks less, it is less likely to ingest another toxin.

“The body goes into a do-or-die, make-or-break mode,” says Hart. “In the wild, an animal can afford not to eat for a while if it means avoiding death. It allows the immune system to get going. You do this – and this is the important bit – before you’re debilitated, when it’s still going to do you some good.”

The next crucial step came from across the Atlantic in Bordeaux. In a series of experiments published between 1988 and 1994, Robert Dantzer, a vet turned biologist, showed three things. First, that inflammatory cytokines in the blood, even in the absence of infection, were enough to bring about sickness behaviour. Second, that these cytokines, produced by immune cells called macrophages, a type of white-blood cell, signal along sensory nerves to inform the brain of an infection. And third, that this signal is relayed to microglial cells, the brain’s resident macrophages, which in turn secrete further cytokines that bring about sickness behaviours: lethargy, depression and loss of appetite.

Dantzer, who has since moved to the University of Texas, had thus dispelled one of the biggest dogmas in neurology – that emotions and behaviours always stemmed from the activity of neurons and neurotransmitters. He showed that in times of trouble, the immune system seizes control of the brain to use behaviour and emotions as an extension of the immune system and to ensure the full participation of the body in fighting infection.

In late April 1996, he set up a meeting in Saint-Jean-de-Luz, on the Bay of Biscay in the southwest of France, to gather together researchers interested in cytokines in the brain. It was there, in a chance meeting over breakfast in the hotel lobby, that he met Hugh Perry, a neuroscientist from Oxford University.

Perry is now at Southampton University. Sitting in his office, surrounded by framed pictures of neurons, his eyes light up as he recounts that meeting with Dantzer. “I remember as he told me about this idea of sickness behaviour thinking, ‘Wait a minute, this is a really interesting idea’. And then when he said that the innate immune cells in the brain must be involved in the process, a bell rang.” He puts down his coffee and rings an imaginary bell above his head. “Ding, ding, ding – so what if instead of a normal brain, it was a diseased brain. What happens then?”

Perry had just started working on a model of neurodegenerative disease in mice. He was studying prion disease, a degenerative disease in the brain, to see how the brain’s immune system responds to the death of neurons. He had switched laboratories from Oxford to Southampton the year after meeting Dantzer and the idea had travelled with him.

He injected his mice with a bacterial extract to induce sickness behaviour, and instead of a normal sickness behaviour response, he saw something extraordinary. His mice with brain disease did substantially worse than those with otherwise healthy brains. They were very susceptible to the inflammation and had an exaggerated sickness behaviour response. They stayed worse even though his healthy mice got better.

This, Perry explains, is because one of the microglial cells’ many roles is to patrol the brain and scavenge any debris or damaged cells, such as the misfolded proteins in prion disease. “When there’s ongoing brain disease, the microglial cells increase in number and become what’s called primed,” he says, referring to the procedure by which the immune system learns how to deal better and more efficiently with harmful stimuli. “When primed, they make a bigger, more aggressive response to a secondary stimulus.”

When the signal of peripheral infection came into the diseased brains of the mice, their microglial cells, already primed, switched into this aggressive phase. They began, as they usually would, to secrete cytokines to modulate behaviour, but secreted them at such high concentrations that they were toxic, leading to the death of neurons.

“But you never really know how your findings will translate to humans,” Perry adds. “So all this mouse stuff could be great, but is there any real importance to it? Does it matter? And that’s when I called Clive.”

Perry hadn’t met Clive Holmes at that point, but had heard of him through Southampton University’s Neuroscience Group, which brings basic researchers and clinicians together. He’d called him in 2001 to ask whether people with Alzheimer’s disease got worse after an infection. The answer was a categorical yes.

“And then Perry asked me if there was evidence to show this,” remembers Holmes. “And I was sure there must be. It was so clinically obvious. Everybody who works with Alzheimer’s just knows it. But when I looked into it, there was no evidence – nobody had really looked at it.”

In several ensuing studies, Holmes and Perry have since provided that evidence. Patients with Alzheimer’s do indeed do worse, cognitively, after an infection. But it’s not only after an infection. Chronic inflammatory conditions such as rheumatoid arthritis or diabetes, which many elderly patients have, and which also lead to the production of inflammatory cytokines, also seem to play an important part.

Holmes and Perry speculate that it’s the presence of the characteristic amyloid beta deposits in the brains of these individuals that primes the microglial cells. And that when signals of inflammation come in, be it from an infection or low-grade chronic inflammatory condition, the microglial cells switch into their aggressive, neuron-killing mode. This, they think, is why removal of amyloid beta might not be working: the damage, or in this case the priming of the microglial cells, might have already been done, meaning that the killing of neurons will continue unabated.

“So next year if these initial results look promising,” says Holmes, “we’re hoping to try and block TNF-alpha in people with the early stages of Alzheimer’s to block this peripheral signal before the disease fully takes hold. We want to see what kind of a dent on disease progression we can get. I don’t know what that’s going to be, but that’s what we’re going to find out.”

If all goes according to plan, and he can secure funding to start the trial at the beginning of next year, Holmes will, by mid-2017, find out for sure whether he can stop the disease taking hold. But the results of his trial in people with late-stage disease, due in the next few months, will give him a strong indication of what to expect.

Noninjectable Insulin Developers Make Progress

Diabetes sufferers may soon be able to avoid the needle.

Noninjectable Insulin Developers Make ProgressLessons from past failures are being applied by drug developers pursuing clinical development of new oral and inhalable insulin products. [AndrzejTokarski/Fotolia]

Whether famous like Tom Hanks or not, millions of people with diabetes for generations have had to take insulin by injection, just as a 14-year-old diabetic named Leonard Thompson did when he became the first patient successfully treated with the peptide hormone in 1922.

Nearly a century later, drug developers remain unable to market a noninjectable therapeutic. But of late, lessons from past failures are being applied by drug developers pursuing clinical development of new oral and inhalable insulin products. The companies see a growing market: An estimated 552 million people are expected to develop diabetes by 2030, up from 371 million in 2012, according to the International Diabetes Federation.

No Needles Required

MannKind earlier this month resubmitted to FDA its new drug application for Afrezza® (insulin human [rDNA origin]) Inhalation Powder for adults with type 1 or type 2 diabetes)—two years after the agency required two additional clinical studies comparing its current inhaler to its first-generation MedTone inhaler.

In August, MannKind released promising results from two Phase III trials. One study in type 1 patients compared Afrezza to insulin aspart; the other measured inhalable insulin in type 2 patients with inadequate diabetes control following metformin treatment, with or without a second or third oral medication. The type 2 study showed a drop in mean A1c levels of 0.82% in patients using Afrezza, compared to a 0.42% decrease in the comparator group. The type 1 study met its primary endpoint of noninferiority to insulin aspart.

Afrezza combines an inhalation powder with an inhaler called Dreamboat™ designed for use by diabetics at the start of meals. The powder dissolves immediately when inhaled to the deep lung and delivers insulin quickly to the bloodstream. According to MannKind, peak insulin levels occur within 12 to 15 minutes of administration, compared with 45 to 90 minutes for injected rapid acting insulin analogs, and 90–150 minutes for injected regular human insulin.

Joseph Kocinsky, MannKind’s svp, pharmaceutical technology development, told GEN Afrezza’s Technosphere® pulmonary drug delivery platform offers competitive advantages. In addition to ultra-fast delivery, insulin administered via Technosphere formulation avoids the hepatic first-pass metabolism that reduces drug bioavailability.

“The Technosphere technology is applicable to a wide variety of drugs (small molecules, peptides, proteins, monoclonal antibodies) and a wide variety of clinical indications like diabetes, pain, osteoporosis, and respiratory disease,” Kocinsky said.

Perhaps Afrezza’s best advantage is the same one offered by the oral insulin products—it doesn’t require a needle. Injection remains no small hurdle to insulin use among people with diabetes, despite improvements over the past generation such as shorter and sharper disposable needles, notes Robert E. Ratner, M.D., FACP, FACE, chief scientific and medical officer for the American Diabetes Association.

Dr. Ratner’s previously work as an investigator included studying Novo Nordisk’s insulin degludec, a long-acting injectable insulin analog. He said injection has one important advantage: Doses can be titrated and adjusted.

“When you’re giving oral or inhaled insulin, that level of precision in terms of dosing is probably going to be considerably harder,” Dr. Ratner told GEN. “We don’t yet know all of the details about the pharmacokinetics of these [noninjectable] agents—how quickly they’ll get absorbed, what percentage will get absorbed, are we going to be able to change the doses to meet the biologic needs of the individual? Those all remain unknowns. Those are the hurdles the companies need to overcome before we have a viable product.”

Road to Success Paved with Failure

Drug developers have long struggled to develop noninjectable diabetes treatments. In 2007, Pfizer stopped marketing Exubera® after 13 months following disappointing sales, took $2.8 billion in pre-tax charges, and returned product rights to partner Nektar Therapeutics.

One key factor in Exubera’s failure was its delivery system: Its inhaler was about a foot long, more conspicuous and clumsier than even the needle. Afrezza can be inhaled through a smaller inhaler requiring no maintenance because it is discarded and replaced every 15 days. Also unlike Exubera, Afrezza is dosed in traditional insulin units that are linear; two three-unit cartridges equal a six-unit cartridge.

Within months of Exubera’s exit, both Novo Nordisk and Eli Lilly ended programs to develop new inhalable insulin products that had advanced to Phase III trials, insisting they had not acted from safety concerns. Lilly brought insulin to market in 1923, and 60 years later launched the first insulin analogs.

Today, Novo Nordisk and another drug developer, Oramed, are well into clinical studies of oral insulin products, with years to go: “We won’t be looking at oral insulin for the next five to six years at the very least.”

Future Possibilities

Also working on noninjectable insulin is Biocon, which last year landed Bristol-Myers Squibb (BMS) as its partner to partially fund Phase II trials of its IN-105 outside India for two years. After that, BMS has the option to assume full responsibility for IN-105, including all development and commercialization activities outside India—in return for BMS paying Biocon a license fee, milestone payments, and royalties on IN-105 sales outside India.

Oramed in July enrolled its first patient in a Phase IIa trial assessing the safety of ORMD-0801, an orally ingestible insulin capsule on patients with type 2 diabetes. A total 30 patients will be enrolled.

“Results of the trial are anticipated by the end of the calendar year,” Aviva Sherman, an Oramed spokeswoman, told GEN.

ORMD-0801 is also under study in a clinical trial in Israel in August that began recruiting patients with type 1 diabetes, for which -0801 is envisioned as a complement to injections, allowing fewer daily injections.

In September, Oramed submitted a pre-IND package to FDA for its ORMD-0901 (oral exenatide), a GLP-1 analog for type 2 diabetes. “By acting on multiple fronts, i.e., stimulation of insulin release and suppression of glucagon release, as well as other actions, GLP-1 addresses diabetes-related glycemia issues on a broader level than does exogenously administered insulin,” Sherman said.

Oramed said its oral insulin mimics insulin’s natural location and gradients in the body by traveling through the gastrointestinal tract encapsulated, then releasing the insulin in the small intestine, from which it is ferried to the liver via the portal vein. The first-pass metabolism significantly reduces the risk of hypoglycemia, the most common side effect of injected insulins.

Novo Nordisk’s candidate OI362GT or NN1954, an oral basal insulin analog intended as a tablet treatment, generated successful results from a single-dose Phase I trial earlier this year. Peter Kurtzhals, svp in diabetes research at Novo Nordisk, told GEN NN1954 is delivered through enteric coated tablets targeting the duodenum, facilitated by the rise in pH that occurs when a substance passes from the acidic milieu in the stomach into the intestine.

“The delivery in duodenum is not more porous, but contents of the gall fluid secreted here may play a role in facilitating absorption of some substances from this part of the gut,” Kurtzhals said.

NN1954 absorption is enabled via partner Merrion Pharmaceuticals’ GIPET® technology. GIPET uses specifically designed oral formulations of patented absorption enhancers designed to activate micelle formation, facilitating transport of drug and increasing absorption.

The drug and enhancer are not bound to each other chemically, but are both ingredients of the tablet, with no interaction between active pharmaceutical ingredient and absorption enhancer. Co-release of the drug and absorption enhancer occurs following dissolution of the coating and a general disintegration of the tablet.

“The oral insulin project is currently in Phase I clinical development. Contingent on successful outcome of these trials, Phase II will be initiated within 1–2 years,” Kurtzhals said.

By the time Novo Nordisk and Oramed complete their required additional trials, followed by formal regulatory reviews, MannKind may have already delivered the first noninjectable insulin to grateful diabetics. Or not. FDA can be expected to show particular caution with noninjectable insulin candidates, given the problems inhalables have had in recent years. To win approvals, companies will have to show not only the usual safety and efficacy, but that their products are better than past noninjectable candidates—drugs young Leonard Thompson could only dream about when he took insulin by needle and made history nearly a century ago.