Infliximab effective after surgery

Research published in Clinical Gastroenterology and Hepatology shows the continuation of infliximab after surgery is effective and useful, even at a low dose.

Patients were given infliximab for three years after surgery, and those with no symptoms then ceased the medication. 83% of those then showed clinical symptoms after a few months, and they were put back onto a low dose of infliximab. This controlled the disease in all patients.

Whilst it's disappointing that most patients were unable to remain in remission without medication, the success of a lower than standard dosage is good news.

Infliximab and Azathioprine combo works best

In October last year I noted a report that Infliximab worked better than Azathioprine, and their combination worked better than Azathioprine alone. A new report in Forbes about a larger, lengthier study confirms the earlier report, and finds that the combination of drugs is significantly more effective than either alone.

After 50 weeks, 72.2 percent of patients who'd received the infliximab/azathioprine drug combination were in steroid-free remission, compared to 60.8 percent who'd received infliximab alone and 54.7 percent who had taken azathioprine alone, according to a Digestive Disease Week news release.

Of additional interest is that the subjects of the study commenced their medication regimes earlier in the disease's progression than is usual. The success of this treatment may influence when these drugs are used in future.

Monoclonal Antibody Decoder

I've created a simple online tool, the MAB Decoder (see the top right of this page) to decode the generic name of any monoclonal antibody. For example, type in the common Crohn's medication infliximab to find from which animal species it is derived, and what part of the body it acts upon. This can be important because human-sourced antibodies are often better tolerated than those from other animals, which may influence your choice of medications. New monoclonal antibodies are being generated all the time, and often you'll see some new ones mentioned in passing. With this tool you simply enter their names to be able to learn more about them.

The MAB Decoder works with generic rather than brand names. Humira, for example, should be entered as adalimumab (the generic name of monoclonal antibodies always end in -mab). Incidentally, it is useful to be familiar with generic names because brand names may vary from country to country.

You can read more about monoclonal antibody naming at Wikipedia.

Although I created this tool to investigate Crohn's drugs, it will decipher monoclonal antibody names for all conditions. You can also try creating your own names, like humungofungomab!

October summary of biologics

Medscape [direct link requires subscription] has released a new summary of the latest findings in biologic therapy for Crohn's disease. Their previous summary on recent anti-TNF research was in June. Although that's still well worth reading, there have been much activity in this area since then.

This article discusses combination therapies, first-line therapy (i.e. should biologics be used earlier in the treatment regime), switching biologics if they become ineffective, safety and newer biologics which have only recently been approved for use. Most of these have been reported in detail previously, but it's handy to have them summarised in one place.

Infliximab more effective than Azathioprine

The Associated Press reports on research that shows Infliximab (Remicade), used alone or in combination with Azathioprine (Imuran) is significantly more effective, and no less safe, than a treatment of just Azathioprine.

Currently, doctors usually prescribe Azathioprine first, and only progress to Infliximab when that fails. This study indicates that Infliximab should be considered earlier. (Note that this study was financed and run by the producer of Infliximab.)

There is more coverage at MedPage Today.

Post AntiTNF biologics

The most recent successfully-introduced medications for the treatment of Crohn's disease, infliximab and adalimumab, have targeted tumor necrosis factor (TNF). However, they are ineffective for some people, and become ineffective in others over time. The Lancet(free registration required) reports some of the different directions that researchers have been examining for further biologic agents, their safety and effectiveness in trials.

Investigators have long sought to identify a micro-organism that causes inflammatory bowel disease. The present theory suggests a breakdown in the balance
between putative species of protective versus harmful bacteria—a notion that has been termed dysbiosis.

Whilst many current drugs reduce the symptoms of Crohn's by suppressing the immune system, research is continuing into drugs that act as immune stimulators.

As a result of decades of intensive research, treatment for inflammatory bowel disease is undergoing a transition from the era of TNF antagonists to an era of novelbiological agents, including those that are able to stimulate the innate immune system.

As you might expect for a medical journal it's quite a technical article, but well worth the effort to see what possible treatments are just around the corner. For easier reading there's a summary at Medical News Today.

Summary of latest anti-TNF research

Medscape (free subscription, or go via Google) has a great in-depth interview with David A. Schwartz, Director of the IBD Center at Vanderbilt University Medical Center, about the latest developments in anti-TNF medications for the treatment of Crohn's Disease. He manages to translate medical-journalese into language that non-medical professionals can understand. It includes important information regarding safety and effectiveness of newer therapies.

Towards the end of the interview he indicates the method of delivery is one important factor in patients' preference for newer biologics over the original infliximab (noting that infliximab must be delivered intravenously by a medical professional, whereas other drugs can be administered by the patient themself at home):

100% of patients who had received both intravenous and subcutaneous anti-TNF therapy preferred the subcutaneous route. The main reasons given for this preference included that the infusions were painful as well as the autonomy that subcutaneous administration provided.

Methotrexate no aid to infliximab

Medpage Today reports the preliminary results of a study which indicated that the common combination of infliximab plus methotrexate is no more effective than infliximab alone. The drugs have very different methods of operation, and are both effective in controlling the symptoms of Crohn's Disease in some people. Until now, it has been commonly believed that the effectiveness of infliximab is improved by concurrent use of methotrexate. However, this report states:

Patients receiving the combination had the same treatment success rate as others treated with infliximab alone in a 50-week, placebo-controlled trial, reported Brian Feagan, M.D., of the Robarts Research Institute in London, Ontario, at Digestive Disease Week.

If further research backs up this finding then there'll be a lot of happy patients who'll be able to reduce the number of injections they need to take. In addition, fewer medications should lead to fewer side-effects.

Steroids as a last resort?

A trial reported in The Lancet (full article by subscription) found that people treated by more aggressive medications earlier achieved better outcomes than those treated in the traditional manner.

Combined immunosuppression was more effective than conventional management for induction of remission and reduction of corticosteroid use in patients who had been recently diagnosed with Crohn's disease. Initiation of more intensive treatment early in the course of the disease could result in better outcomes.

As explained by The Globe and Mail:

Traditionally, patients diagnosed with the devastating inflammatory bowel disease are treated with a "step-up" approach, a series of drugs given sequentially as their health deteriorates.

First, they get corticosteroids to control symptoms like abdominal pain and bloody diarrhea. They are then prescribed a powerful immune-suppressing drug, which prepares them for a third medication, an antibody that curbs the inflammation at the root of the disease.

This study shows that reversing the conventional order, using infliximab as the initial treatment, could provide better long-term results. Coincidentally, the more aggressive medications are typically much more expensive, though the improved results could outweigh this with lower overall medical costs.

I don't see this report as leading to any treatment changes in the near future. The inertia of conventional treatment requires larger, longer-term trials to be overturned. However, after the positive results of this report, I'm sure just such trials are being planned.

Updated 21 March 2008: The (Canadian) National Review of Medicine mentions that there is a larger study already in progress.

Infliximab subsidised in Australia

The Sydney Morning Herald reports, as predicted, that Infliximab will be available on the Pharmaceutical Benefits Scheme (PBS) from October for the treatment of Crohn's disease. Prior to this patients would have to pay the thousands of dollars themselves, or be one of the lucky few paid for by a hospital.

Long term effects of anti-TNF

A great editorial in the Annals of Internal Medicine discusses how the the two current anti-TNF treatments, infliximab and adalimumab, are not living up to their initial promise.

The article examines the latest research into the effectiveness of these antibodies, and notes that responses to infliximab lessen over time. It adds that people who have stopped responding to infliximab will then not respond as well as other people to adalimumab, and they ponder whether the infliximab has changed the underlying nature of the Crohn's disease.

I thoroughly recommend this as required reading for Crohn's patients who are considering starting on an anti-TNF regime.

Infliximab may soon be subsidised in Australia

The Australian Pharmaceutical Benefits Advisory Committee has recommended that Infliximab (Remicade) be subsidised for the treatment of Crohn's disease (it's already subsidised for other conditions):

The PBAC recommended the listing of infliximab for the treatment of patients with severe Crohn’s disease (Crohn’s Disease Activity Index ≥ 300) or patients with an ileostomy or colectomy due to Crohn’s disease on the basis of a high but acceptable cost-effectiveness ratio compared to placebo. Acceptable cost-effectiveness was demonstrated at a dose of 5 mg/kg infliximab for three doses (weeks 0, 2 and 6) and when continuation of treatment beyond three doses was determined by remission (CDAI ≤ 150) at approximately 12 weeks from the commencement of treatment.

As noted by the Sydney Morning Herald it still has to be approved by the government. If they do so, then the cost per injection will be reduced from $4000 to a much more manageable $30.

Humira nears US release for Crohn's

The Boston Globe has an update on new medication that is expected to be released to US consumers soon. Crohn's afflicted people outside the US will probably welcome this news, as it will introduce a large new population for the drugs to be tested on. It'll be interesting to see if Humira lives up to its promise of providing longer-term remission than infliximab (Remicade).

Within days, Illinois-based Abbott Laboratories expects to win federal approval to sell its drug, Humira , currently used to treat rheumatoid arthritis, psoriatic arthritis, and a disease that causes arthritis of the spine, to combat the intestinal disorder.

...

In clinical trials, 21 percent of patients who had stopped responding to Remicade were coaxed into remission by week four on Humira, compared with 7 percent who achieved remission on a placebo. Those results were impressive enough for the FDA to speed its handling of the drug -- trimming the review from 10 months to six months and indicating that an approval decision could come by the end of February.

Recent developments

Hidden behind the subscription wall of The Wall Street Journal is a nice summary of the current status of the various Crohn's treatment options. That article has now made its way into the free world via the naplesnews.com.

Amongst developments not yet reported in this blog is news of medicine which is potentially better than the highly-regarded anti-TNFs gaining popularity today. These include arthritis drug Orencia, interleukin-12 and interleukin-23 (interleukin has been mentioned previously), and a drug using adult stem cells.

Besides anti-TNFs, there is a rheumatoid arthritis drug from Bristol-Myers Squibb, called Orencia, that is being studied for Crohn's disease. The drug works on inflammation earlier in the process than do anti-TNFs. Bristol started the final phase of human testing of Orencia against Crohn's last month and is currently enrolling patients in a trial.
...
J&J and Abbott are working on drugs that inhibit two proteins called interleukin-12 and interleukin-23. Both companies are in the middle stages of human testing. Strober, of the National Institute of Allergy and Infectious Diseases, says the benefit could be tackling inflammation much earlier in its development than the anti-TNFs do, but that the drugs could carry an increased risk of infection.
...
Osiris Therapeutics, based in Baltimore, just got approval from the FDA to go into the third and final phase of human testing on a Crohn's drug that uses adult stem cells. The company says the agency gave the drug fast-track status, which means it could come to market as early as 2008.

The drug is thought to work by correcting inflammation only where it's taking place — which could help avoid excessive immune suppression.

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.
...
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.

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.