Natalizumab potential for Crohn's downplayed

The Boston Globe reports that it is unlikely that natalizumab (marketed as Tysabri) will be a viable treatment for Crohn's disease. Earlier reports had looked promising.

Biogen Idec's chief executive, James Mullen, says the Cambridge biotechnology company is unlikely to receive approval from European regulators to use its drug Tysabri to treat patients with Crohn's disease, a debilitating intestinal ailment.
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In a comprehensive safety review last year, the companies found two multiple sclerosis patients with PML who were also being treated with Biogen Idec's drug Avonex, another treatment for multiple sclerosis. One of those patients survived. Another patient in a Crohn's trial, who died from PML, had been treated with immunosuppressants.

That pattern suggested the risks of contracting PML while using Tysabri could increase if a patient is also being given a drug that affects the immune system. If so, that raises the risks of treating Crohn's patients with Tysabri, because many have weakened immune systems.

"Against the backdrop of PML, where you have a set of patients that already get bombarded with immunosuppressants over 20 to 30 years, [Crohn's] is not the first place we'd go to develop Tysabri," said Mullen. He said the drug looks more promising as a treatment for Lupus and certain cancers.

CBC News has further details from a north American perspective:

Caroline Stewart, an industry analyst for Piper Jaffray, said it would be difficult for Biogen Idec and Elan to match sales of the leading Crohn's treatment, Johnson & Johnson's Remicade, given Tysabri's PML risk.

"I think the sales in Crohn's are going to be limited, because it's not a life-threatening disease, and the potential side effects of Tysabri are life-threatening," Stewart said.

Vaccine hope

The Scotsman has a very optimistic article about a Crohn's vaccine that seems to work in mice:

John Hermon-Taylor, professor of surgery at St George's Hospital in London, believes he has made the breakthrough that could spell the end of the incapacitating disease.

Prof Hermon-Taylor has conducted pre-clinical vaccine tests on mice and says preliminary results returned no signs of side-effects or adverse reactions.

He said: "The vaccine proved highly successful in both treatment and prevention in pre-clinical trials.

Lest everyone gets their hopes up too high, as far as I'm aware, the theory on which this vaccine is based, stated in the article as fact, is still unproven:

Crohn's is a severe inflammation of the small intestine and the colon that can require surgery. It is caused by the bug MAP (Mycobacterium avium subspecies paratuberculosis), which is widely carried and contracted by farm animals.

Still, I have my fingers crossed that vaccine is a success in humans.

Interleukin receptor mutation found

A variety of media outlets have covered the new research that has found a gene mutation relating to the inflammation protein interleukin-23. (The roles of the different interleukins are summarised in the Wikipedia.) In this study, the DNA of people with Crohn's was compared with that of people without Crohn's. A mutation in the interleukin-23 receptor was one of their findings.

The BBC notes:

The fault is in a gene receptor present in healthy people without inflammatory bowel disease but rare in those with the condition.

Further background is provided by the Baltimore Sun:

In 2001, scientists identified the first major gene underlying Crohn's disease. Called Nod2, the gene regulates the immune system's response to bacteria in the gut. People with one flawed copy have twice the normal risk of developing the disease, researchers found. Two flawed copies and the risk jumps 20- to 40-fold.

Researchers have since uncovered a handful of other suspicious gene mutations thought to play a role in inflammatory bowel disease. But the new finding marks the first time researchers have identified a mutation that may actually help protect against Crohn's.

The potential result of this finding is better drug therapies, eventually.

Natalizumab long-term remission results

Elan and Biogen Idec announced that a trial has found that natalizumab (sold as TYSABRI) maintained remission in Crohn's disease patients treated for longer than 2 years.

93% of TYSABRI patients who were in remission at month 12 of ENACT-2, were still in remission following 6 additional TYSABRI infusions in the open-label extension study and 86% were still in remission after 12 additional infusions.

These results were based on approximately 90 patients who were in remission after 15 months of continuous TYSABRI therapy in the ENACT-1 and ENACT-2 trials and elected to enroll in an open-label extension trial. A subpopulation of 22 patients was previously exposed to infliximab therapy. In this subpopulation, 91% were in remission after additional 6 and 12 infusions of TYSABRI, and 82% who had previously failed therapy with infliximab were in remission at the same time points.

"What is truly exciting is that patients who enter remission on TYSABRI may remain in remission in the long-term without loss of efficacy over time. These data are a significant advance for the field and suggest that TYSABRI may be an alternative biologic outside the anti-TNF class for patients suffering from Crohn's disease," said Remo Panaccione MD, Director, Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, Canada, who presented the data at UEGW.

Natalizumab, like infliximab, is a monoclonal antibody (all generic medicine names ending in -mab are monoclonal antibodies). It is also used to treat multiple sclerosis, but was withdrawn from market in 2005 due to safety concerns. In mid 2006 it was reapproved for use in the US and Europe. More details are in the Wikipedia.

Prochymal phase II trial results

Osiris Therapeutics have announced encouraging results from their small trial of Prochymal in patients who had failed to respond to standard treatments.

Prochymal is a preparation of mesenchymal stem cells specially formulated for intravenous infusion. The stem cells are obtained from the bone marrow of healthy adult donors.

Comments were made by the lead investigator, Dr. Jane Onken:

“To understand the significance of this trial, it is important to appreciate just how sick these patients were,” said Dr. Onken. “On average, they had suffered with Crohn’s disease for 14 years and were unable to find relief with currently available therapy. It was in this difficult-to-treat population that we observed clinical improvement upon administration of the stem cell therapy.”

The Baltimore Sun had a talk with one of the participants of the trial:

The change, he said, began sometime in May, about eight weeks after he'd received an experimental stem-cell treatment developed by Baltimore's Osiris Therapeutics, which yesterday announced results of the 10-person clinical trial Gagne took part in.

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"I have hopes, but I'll be very candid. I've been on other treatments as long as 13, 14, 15 months that worked reasonably well. The vote is still out on this," he said. "Right now, it's probably the best treatment that I've ever had based on the results that I've achieved, but [I'm waiting to see] if it works like this for, let's say, 15, 16, 24 months."

The Baltimore Sun has further details in their business section.

Prochymal, which Osiris says interacts with immune cells to reduce inflammation and aid tissue repair, already is in late-stage trials as a treatment for a rare inflammatory condition associated with bone marrow transplants. If approved, it would likely be the first pure stem cell product on the market.

What is Cimzia?

The last time I mentioned Cimzia it was so new that I couldn't find any information about how it actually worked. Now, that august journal of medical knowledge, BusinessWeek online, fills in the gaps, in an interesting interview with the CEO of Cimzia developer UCB, Roch Doliveaux:

BW: Analysts reckon Cimzia has blockbuster potential. What other Crohn's disease drugs are on the market, and how is Cimzia different?

RD: The biggest rivals are Remicade from Johnson & Johnson and Abbott's Humira, a drug currently approved for use in rheumatoid arthritis that's expected to gain additional approval for use in Crohn's.

Both of these drugs are monoclonal antibodies, which are derived from very large molecules. These drugs require a lengthy, complex, and expensive manufacturing process. Because they're large molecules, they tend to penetrate tissues poorly, so they must be administered by injection. Also, these larger antibodies can often trigger unwanted immune responses.

In contrast, Cimzia is the next generation of antibodies. We use the smallest possible fragment of an antibody, called a nanobody. As these nanobodies are much smaller, they're able to penetrate tissue in the body more easily. The big advantage with nanobodies, we believe, is that it requires a much simpler manufacturing process, which means that over time it will be a lot less expensive than monoclonal antibodies to produce.

The way Cimzia is administered is also unique. While Remicade is given by an intravenous infusion at the doctor's office or hospital, Cimzia is the first Crohn's drug that is able to be given by injection through the skin. It's similar to the way diabetics are able to self-inject insulin.

Of course, if they made it into a pill instead of an injection, they'd get an even more enthusiastic response. However, the ability to inject yourself at home is a massive advantage over endless visits to the doctor.

Where'd my gene go?

The German Cancer Research Center, DKFZ have an article which describes a possible genetic cause of Crohn's disease.

Patients with Crohn’s disease of the colon have one copy less than healthy persons of the beta-defensin 2 gene, a gene coding for an important defense molecule of the body.

[...]

Defensins are part of the arsenal of defense weapons used by the human immune system. [...] Patients with Crohn’s disease of the colon (colonic CD) have a lower level of beta-defensins in the mucous membranes.

Defensin genes are arranged in nests, called clusters, on chromosome 8. The number of clusters varies considerably across the population; this is technically called a polymorphism. The research team has now shown that patients with colonic CD have on average only three copies of the gene encoding beta-defensin 2, whereas healthy control persons as well as patients with small bowel CD or ulcerative colitis, another inflammatory bowel disease, have an average of four copies of this gene per cell.

The researchers showed that a lower number of gene copies is indeed associated with reduced production of the endogenous antibiotic, which explains the known low defensin level. They presume that this causes the defense of the intestinal mucous membrane to become porous so that bacteria can attach to and invade the mucous membrane, which leads to the typical inflammatory hot spots of Crohn’s disease.

The purpose of the defensin is described by MedicineNet as:

A family of potent antibiotics made within the body by neutrophils (a type of white blood cell) and macrophages (cells that can engulf foreign particles). The defensins play important roles against invading microbes. They act against bacteria, fungi and viruses by binding to their membranes and increasing membrane permeability.

The DKFZ work is an extension of earlier research published in PNAS which examined the connection between Crohn's disease and reduced defensin levels.

The pathogenesis of Crohn's disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human {alpha}-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC {alpha}-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CD of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC {alpha}-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of {alpha}-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of {alpha}-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and/or perpetuate this disease.

Naltrexone shows positive results

Penn State Live reports that a pilot study has shown encouraging results in using naltrexone to treat Crohn's disease.

In the study, patients with diagnosed Crohn's disease were treated with a low dose of naltrexone, an FDA-approved drug used to ease symptoms of withdrawal from substance abuse, and monitored for improvement of symptoms for 12 weeks. Quality of life surveys were given every four weeks for 16 weeks.

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The results showed that 89 percent of participants showed an improvement with therapy, while 67 percent achieved remission of symptoms. The only side effect to treatment was sleep disturbance in some patients.

In addition to combatting drug and alcohol addiction, naltrexone is also used to treat multiple sclerosis (though its effectiveness has yet to be proven), which like Crohn's is a disease of the immune system.

Good results for Humira

Abbott has announced that a trial has shown that people for whom Humira (adalimumab) is effective after four weeks who then take Humira either weekly or fortnightly for a year are much more likely to be in remission after six months and after year than those taking a placebo. There's a lot more detail in the press release.

In addition they include interesting news for users of infliximab (Remicade), mentioning:

Abbott has received FDA approval to initiate a Treatment Protocol to study the use of adalimumab in patients no longer responding to or intolerant to infliximab, an approved therapy for Crohn's disease.

Self-medication with hookworm

Kuro5hin has an intruiging first-hand tale of a person who cured his asthma by deliberately gaining and maintaining a hookworm infestation. Although this has been proposed as a possible treatment for Crohn's and other auto-immune diseases, the necessary extensive research has not yet been done. In addition, if it is found to be effective, then the particular mechanism that the hookworms use would be analysed and, if possible, turned into a much safer medicine than being a host for parasitic organisms.

Based upon what I read, and what I learned about the hookworm I decided that I was going to try and infest myself with hookworm in an attempt to cure my asthma. I was not willing to wait ten or more years for the drug companies to bring a drug to market. It was obvious to me that hookworm, for a healthy adult with a good diet, are quite benign.
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At this point I came to the conclusion that short of bribing a research assistant or stealing samples from a lab I would have to go to the tropics and walk around barefoot in human excrement. Not an attractive proposition, but then neither is not being able to breathe, and the breathing thing was going to last the rest of my life.

But where to go to find these hookworm?

Intensive searches of the WHO website turned up just one map showing hookworm distribution in only one country: Cameroon.

Remicade for children with Crohn’s Disease

The FDA's priority review program has lived up to its name, as only a month since being accepted into that program the Food and Drug Administration has approved the use of Remicade (Infliximab) for children with Crohn's Disease. The trial they examined showed that the medicine was as effective in children as in adults, and that it had the same side-effects.

Remicade is a genetically engineered monoclonal antibody, which reduces inflammation (swelling/redness) by blocking the action of tumor necrosis factor-alpha (TNF-α), that was initially approved in 1998 to treat Crohn's disease in adults.
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The safety and effectiveness of Remicade in pediatric Crohn's disease were assessed in a randomized study in 112 children who were 6 to 17 years old with moderately to severely active Crohn's disease who had an inadequate response to conventional therapies. The proportion of these patients who achieved clinical response compared favorably with the proportion of adults in an earlier Remicade study in adult Crohn's disease, and the pediatric trial's results showed no new safety concerns not already expressed in the product's current label.

In other news relating to Remicade and its sibling Humira, the Washington Post notes that serious side-effects have recently been reported in adults:

Approval comes after Wednesday's publication in the Journal of the American Medical Association of a study in which researchers said they found an apparent link between Remicade and a second drug, Humira, and some types of cancer in rheumatoid arthritis patients. Those cancers include skin, gastrointestinal, breast and lung tumors.

The FDA-approved labeling for Remicade, also called infliximab, already mentions the drug's association with an increased risk of lymphoma and other cancers, including skin, breast and colorectal, the regulatory agency and the drug's manufacturer both said. The label also mentions an increased risk of serious and sometimes fatal infections, as well as disorders of the blood and central nervous system.

Update 23-May-2006: Abbott, the manufacturer of Humira, has responded:

The conclusion in the JAMA article regarding risk of infection in those taking anti-TNF agents restates what has already been observed in the clinical trials of all three anti-TNFs. These data have been reviewed in a U.S. Food and Drug Administration (FDA) Arthritis Advisory Committee meeting in March 2003, and routinely since that time. The information in the JAMA article on infections is well documented in the labeling of all three anti-TNF agents, including HUMIRA (adalimumab).

Abbott disagrees with the authors' conclusions that their analysis establishes an increased risk of malignancies attributable to the anti-TNF agents included in their meta-analysis. The potential role, if any, of TNF-blocking therapy in the development of malignancies is not known, and this is reflected in the labeling of all three agents.

NACC - Ongoing research

While there's a lull in research results being announced it's an opportune time to point out one of the sources of the research.

The UK's National Association for Colitis and Crohn's Disease (NACC) has been funding research for a number of years, and the targets of their recent research funding are succintly described in plain English on their research pages. In addition there is a comprehensive summary of NACC research since 1984 which is well worth reading.

Other national Crohn's and Colitis associations distribute research funding, but none are as successful as the NACC in communicating the relevant details to the general public.

Remicade moves closer to approval for use on children

Johnson & Johnson announced that REMICADE for the treatment of Crohn's disease in children has been accepted for Priority Review by the U.S. Food and Drug Administration (FDA).

The filing is based primarily on Phase 3 study results showing the unprecedented efficacy of REMICADE® in the treatment of children with moderately to severely active Crohn's disease. In the REACH [...] trial, nearly 90 (88.4 percent) of pediatric patients with moderately to severely active Crohn's disease who had an inadequate response to conventional therapy achieved clinical response at week 10 when treated with REMICADE®. Nearly two-thirds (63.5 percent) of the patients who were randomized to treatment with REMICADE® every eight weeks were in clinical response at one year. Additionally, more than half of the patients treated with REMICADE® every eight weeks were in clinical remission at the end of one year.

Priority review is explained by the FDA:

Prior to approval, each drug marketed in the United States must undergo a detailed FDA review process. The FDA has been classifying the likely benefit of a drug since the 1970s, initially in three categories: (A) a major advance over available treatments, (B) a modest advance, or (C) no real advance. More recently, the classification has been in two categories: a real advance (priority or P), or about the same effectiveness as available therapies (standard or S).

In 1992, under the Prescription Drug User Fee Act (PDUFA), a law that requires fees be paid by drug manufacturers when they submit an application to market a drug, the FDA agreed to specific goals for completing its review and taking action on drugs. These goals were different for priority and standard drugs.

For standard drugs, which offer at most only minor improvement over existing approved therapies, review and action were to be completed in 12 months. The 2002 amendments to PDUFA changed that goal to 10 months.

Priority drugs, or those that offered a significant improvement over marketed treatments or provided a treatment where no adequate therapy existed, were given a six-month review and action goal.

CIMZIA submitted for US FDA approval

UCB put out a press release announcing their submission for approval of a new anti-TNF drug. They note that:

If approved, CIMZIA would be the first-ever biologic utilizing subcutaneous injection for the treatment of Crohn's disease.

To lightly paraphrase their results, data from PRECiSE 2 (the second of four studies) demonstrated that within six weeks of initiating CIMZIA, 64.1 percent of patients achieved a clinical response.

At the end of 26 weeks, significantly more patients, 62.8 percent on CIMZIA vs. 36.2 percent on placebo, maintained an overall clinical response. Additionally, at 26 weeks, significantly more of CIMZIA patients were in clinical remission compared to placebo patients. CIMZIA was generally well tolerated with an adverse event profile similar to other anti-TNF agents.

Reuters adds:

Cimzia will compete against Johnson & Johnson's Remicade in the Crohn's market and against Amgen's Enbrel and Abbott Laboratories' Humira -- as well as Remicade -- in arthritis.

Teduglutide trial promising

Yahoo has a press release about a small study into an interesting experimental drug Teduglutide:

Overall, the study results showed a positive and consistent trend toward efficacy and a dose response favoring the highest dose group: 36.8% of patients receiving the highest dose of teduglutide reached clinical remission (Crohn's disease activity index (CDAI) score of less than 150 points) at week two versus 16.7% of the placebo group, while 55.6% of patients in the highest dose group reached clinical remission by week eight compared to 33.3% of the placebo group. Teduglutide was well tolerated with no serious adverse events related to the drug.

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Teduglutide is a proprietary analog of glucagon-like peptide 2 (GLP-2), a naturally occurring hormone that regulates the growth, proliferation and maintenance of cells lining the gastrointestinal tract. A previous Phase 2 clinical study in patients with Short Bowel Syndrome showed that daily subcutaneous injections of teduglutide resulted in significant growth of the intestinal lining and improved dietary absorption of nutrients and fluids.

Crohn's due to weakened immune system

The BBC reports on a Lancet study that indicates that Crohn's may be due to a "weakened immune system failing to destroy bacteria".

The UCL team compared the immune system response of Crohn's patients and healthy individuals to minor injuries, such as skin abrasions.

They found the Crohn's patients produced much lower numbers of infection-fighting white blood cells called neutrophils, and lower quantities of chemicals involved in the inflammatory process.

...

The researchers believe that, because Crohn's patients have weakened immune systems, they are unable to destroy bacteria that penetrate the intestinal wall.

Thus the bacteria are left to build up in the tissue, stimulating the secretion of inflammatory chemicals that trigger the symptoms of Crohn's.

Forbes has further specific information:

Segal and his colleagues measured the number of neutrophils (white blood cells) produced by Crohn's patients in response to trauma in the bowel and on the surface of the skin.

Surprisingly, these patients produced 79 percent fewer neutrophils and inflammatory mediators compared with healthy individuals subjected to the same trauma.

When a harmless form of bacteria was injected under the skin, blood flow in healthy volunteers increased tenfold over 24 hours. But in people with Crohn's disease, blood flow increased only fourfold.

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But others feel that the work does not really break new ground. "There have been other studies in the last year or two that Crohn's disease is really a problem dealing with bacteria in the colon and the inflammation is set up because there's more of a defective immune response to the bacteria in the gut," said Dr. John Thompson, director of the division of pediatric gastroenterology and nutrition at the University of Miami's Miller School of Medicine.

The link between Crohn's and MAP

The Saturday Evening Post has an in-depth interview with leading researcher and advocate on the link between Crohn's and MAP, Dr. John Hermon-Taylor.

He explains why he believes there is a link between Crohn's and MAP and describes the success he has had in treating Crohn's patients.

Using the polymerase chain reaction (PCR) technique, you can show that virtually everyone with chronic inflammation of the Crohn's disease type is infected with the MAP bug. MAP is an organism that is a specific cause of chronic inflammation of the intestine in many different species of animals, including primates.

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There are now four open-label clinical studies carried out independently ... which essentially all say the same thing. That is, that somewhere between 50 to 75 percent of people with active Crohn's disease who can take rifabutin and clarithromycin treatment will get better and heal--sometimes like magic.

COX-2 inhibitors for pain-relief?

EurekAlert has a release about the results of two research programs into the use of COX-2 inhibitors by people with IBD:

Both studies examined the benefits of non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, in a patient population with ulcerative colitis and/or Crohn's disease. Study findings show that NSAIDs were well-tolerated, with COX-2 inhibitors offering the most effective pain relief in this group.

MedPage Today has another summary:

... these studies imply that NSAIDs -- long thought to be absolutely contraindicated for patients with inflammatory bowel disease -- can be used safely in some circumstances

Sargramostim trial

Australia's ABC News is reporting that use of cancer therapy drug Sargramostim in trials for Crohn's disease is showing good signs:

... Dr Graham Radford-Smith from the Royal Brisbane Hospital says the outlook is positive.

'The important things are that this drug is very safe, it's got a long track record, it's been around for a long time, there have not been any major safety issues,' he said.

'We're yet to see what happens in terms of efficacy and that's obviously critical in the drug being successful in the treatment of Crohn's disease.'

According to the Yahoo Health Drug Guide:

Sargramostim is used to increase white blood cells and decrease the risk of infection in conditions such as cancer, bone marrow transplant, and pre-chemotherapy blood cell collection.

The New England Journal of Medicine has the full report of another trial of Sargramostim for Crohn's disease. Though the report costs money to view, the quite detailed abstract is free to read. Its conclusion was interesting:

This study was negative for the primary end point, but findings for the secondary end points suggest that sargramostim therapy decreased disease severity and improved the quality of life in patients with active Crohn's disease.