Are Placebo’s Getting More Effective?

At least some people believe they are – particularly those drug companies whose pipeline champions are being sunk by the famous effect. This Wired article offers a great list of drugs recently entombed by the placebo effect. It also explains it’s history and the concern it is causing in drug development. But I disagree that the placebo effect is ‘increasing’ as they suggest.

The drop in drug approvals they cite and many of the specific examples they give are probably not due to an ‘increasing placebo effect’ but poor trial design, less effective new therapies and the lack of low hanging fruit. I would even suggest that the perceived change in the effectiveness of Prozac is actually the result of better experimental measurement leading to better data that demonstrates what clinicians have always known.

Trials are becoming harder to design as there is less money available – in part because potential profits from new drugs are not what they used to be. Studies are ‘powered’ at an absolute minimum, and resources sent offshore to clinics with high capacity but lower quality guarantees. This is of particular concern in studies where drug efficacy is highly dependant on patient or clinician reporting rather than hard measures such as well defined lab tests. They Merck scientist in fact demonstrates this when he says they saw different effects in Spain and France.

They author also fails to mention that many new drugs being trialled are in therapeutic areas fairly well served by existing drugs. there is less room for improvement and therefore it is harder to create more efficacious drugs. Early phase testing is easily misleading due to small sample size and other biases.

When the article delves into the cognitive neuroscience behind the placebo effect they indeed point to the fact that by definition, the placebo effect can’t ‘increase’ unless the human brain changed substantially in the last 40 years.

Despite this it is a great article and I look forward to hearing more about the Placebo Response Drug Trials Survey.

Clinical Trials Evolving

A NYTimes article, Lack of Study Volunteers Is Said To Hobble Fight Against Cancer, gives some stark statistics about the diminishing availability of patients for cancer trials, and hints at some of the broader problems in the world of clinical trials.

At a recent NHMRC Clinical Trials  meeting, several presentations dealt with the changing nature of clinical trials. The main challenges presented were:

1. Trials are being moved by companies to developing countries where trials costs are cheaper and more patients available.
2. Fewer trials are for drugs that will demonstrate significant improvements in efficacy. This in turn means larger numbers of patients are needed for the trial to demonstrate superiority.
3. New technology, particularly biomarkers, are both a benefit and a challenge as subpopulations of responders are identified and trials endpoints need to be shifted.

Overall, the feeling was that the current trial paradigm is far to rigid and expensive. The NYTimes article alludes to this strongly. One impressive stat they cite was that there are more than 6,500 cancer clinical trials seeking adult patients, according to clinicaltrials.gov. But more than one trial in five sponsored by the US National Cancer Institute failed to enroll a single subject, and only half reached the minimum needed for a meaningful result (reported in a recent review in The Oncologist). At California Cancer Care, in Greenbrae, north of San Francisco, they try to offer trials to every patient. Yet last year they enrolled just 43 of about 700 new patients.

While the US has it’s own health care issues that are partly impacting on trial uptake, these are ominous signs – to some.

My view is that these changes are part of the new world of drug development. We are moving towards streamlined naturalistic trials in a world replete with real-time patient outcomes data. The faster we run out of pointless trials for me-too drugs, the better.

A Public Drug Library

From Fiercebioresearcher:

The Johns Hopkins University School of Medicine has one of the largest public drug libraries in the world. And the stockpile of more than 3,000 drugs has proven a fertile field for researchers exploring new uses for old compounds.

Exploring the stacks has revealed that itraconazole–used to treat toenail fungus–may be effective against tumors as well as macular degeneration. And the leprosy drug clofazimine may also be effective against MS and psoriasis. “It takes 15 years and costs close to a billion dollars to develop a new drug,” pharmacology professor Jun O. Liu tells the New York Times. “Why not start with compounds that already have proven safety and efficacy?”

Liu and colleagues have been building the library for seven years and say it will be done in another two. And they are providing researchers with samples of a complete set for $5,000.

Scientists Mine Drugs Database for New Diabetes Treatment

From: http://www.biocompare.com/News/NewsStory/263918/NewsStory.html

Scientists have harnessed a new drug discovery tool to identify a new player in the body’s insulin secretion process. This finding could spark a completely new class of drugs to treat type 2 diabetes.

In work published today (22 February) in Nature Chemical Biology researchers at the University of Oxford explain how they have exploited new technology to create a cheap and efficient method of drug discovery that will allow small academic labs to search a large database of drugs to find treatments for diabetes and many other diseases. They have used this new method to identify a small molecule which they are using to understand how insulin is secreted in response to increases in blood sugar.

Lead researcher Dr Grant Churchill said: “A lot of diseases are caused by problems with important proteins within cells. We need to find small molecules that change the function of these proteins both to discover how they work and in addition because these small molecules may also work as treatments for disease. The approach we have developed allows us to do this much more quickly and cheaply than many of the current methods. Ultimately this will speed up the process of getting better treatments into the clinic for patients.”

Starting with a natural chemical and systematically modifying its chemical structure is a proven technique and common drugs such as beta-blockers and anti-histamines were discovered this way. However, these discoveries involved lengthy chemical syntheses starting with the natural chemical (adrenalin and histamine respectively).

“Our method also begins with the natural chemical but rather than modifying it with a time-consuming and expensive chemical syntheses conducted by a team of chemists, ours uses computers to identify corresponding small molecules for research and medicine. The major difference is that we have linked the computational methods commonly used by pharmaceutical companies to a freely available database of 5 million existing compounds – the ZINC database. This means we cut out a hugely time consuming and financially intensive part of the process, which is difficult for small academic labs to do,” Churchill said.

The team has tested their method by successfully identifying a small molecule called Ned-19. This molecule was found after information about the natural chemical NAADP was entered into the computer system and cross referenced with the ZINC database. In collaboration with scientists at the University of Southampton, led by A.Ganesan, Ned-19 was prepared on a larger scale and separated. Further experiments were carried out with these compounds to confirm the activity of Ned-19. Using Ned-19 in experiments they have discovered that NAADP plays a crucial role in insulin secretion and therefore represents a brand new target for diabetes drugs.

The Next Class of Blockbuster Drugs?

The power of antibodies is well established. but their cost is often prohibitive in a world of already stretched health budgets.

The solution to this conundrum may have appeared. Mini or nano-antibodies from llama, camels, shark and other animals have been the subjected of much research for some years.

These animals, including the camelid family,  produce functional antibodies devoid of light chains of which the single N-terminal domain is fully capable of antigen binding. These single-domain antibody fragments (Nanobodies) have several advantages for biotechnological applications. They are well expressed in microorganisms and have a high stability and solubility. They might be administered orally, solving another of the great problems with ordinary antibodies which require regular injection.

 

These nano-antibodies look particular interesting for the treatment of cancer, inflammatory conditions and blood disorders. Clinical trials of several compounds are already underway.