Episode 28: Placebo Your Bets
If you missed previous episodes of the biotech-themed soap opera "All My Clones," click here to read the beginning of the story.
Rupert Madasheck was worried. As CEO of Cappuccino Pharmaceuticals, he relied on scientists outside the company to provide him background to feign an understanding of the therapeutics space. It was not encouraging to find a mentor's name in the papers for fraud.
Rupert's source, Gotchaberg, had discovered an apparent prostate cancer biomarker in rats some years before. When investors formed a company based on his discovery, Gotchaberg claimed he found a human homologue and was developing an immunoassay. The company, Onocrudde, now believes there is no human protein and no test.
I thought I smelled a rat! Rupert thought as he crossed Gotchaberg off his list.
Effects of the Placebo Effect
Betty Lidalot felt it was a good day to be alive and to be the chair of Cappuccino, good enough to stop in and ask Rupert, "How's it going with the Placebolomics project?" (See "All My Clones," Episode 20.)
Rupert beamed. "Great! We're negotiating deals with several companies that found amazing placebo effects in their trials. There's Rigel, Targacept, Osiris Therapeutics, Acadia Pharma, Biovail, Array Biopharma, Memory Pharma ..." (See BioWorld Insight, Sept. 7, 2009.)
"Wasn't there one from big pharma?"
Rupert sneered. "There's those Lilly-livered people at BioMS, after the Phase III MS drug trial failed." (See BioWorld Today, July 29, 2009.)
Betty could not believe companies were still failing to weed out bad candidates early. "How did they get as far as Phase III? Why did it fail?"
"Funny you should ask — the CEO announced, 'We're not quite sure.'"
CSO Dr. Wyllie stepped in to add, "He also said it was 'probably the lowest rate of progression ever seen in a placebo group in an MS trial.'"
"What a coincidence — yet another astonishingly potent placebo effect!" Betty couldn't believe it.
Irreproducible Results of Skewed Trials
Wyllie tut-tutted, "Not so fast! The BioMS chair's wife has been taking their drug and responds just fine. So they're trying to design a trial that shows the awesome power of their drug."
Could that be true? Betty asked herself. "Yes, a sample size N = 1 certainly proves the hypothesis, doesn't it? There was an article in the Journal of Irreproducible Results to that effect ... So let's see, with our Placebolomics platform, we have drug candidates for Parkinson's and Alzheimer's disease psychosis, MS, rheumatoid arthritis, Crohn's, graft-vs.-host disease ... that's quite a product line."
"Still, we need to understand the underlying biological basis for our drugs," Rupert cautioned. "I'm sure inquiring minds at the FDA want to know!"
"What? They're all just the same sugar pill!" Betty exclaimed.
Wyllie spoke up quickly. "Please! We are dealing with world-class organizations here. In spite of, say, FDA approval for BiDil with no idea why it would preferentially benefit African-Americans. Some of these trials require a questionnaire to assess the patient's perceived response." (See BioWorld Today, June 27, 2005.)
Betty shook her head. "Bad idea asking a patient what she thinks!"
"Just so," conceded Rupert. "Osiris thinks patients in early trials respond so they will get to stay in later trials."
"Better yet, Array's CEO notes that placebo effects are huge in what he called non-Western countries," noted Wyllie. "It could be that the general conditions and care during a trial are significantly better than people's standard of living. So they feel much better even with no specific drug-related improvement."
"Wait until they realize some of the questions were maliciously mis-translated into Spanish and Polish into, 'Do you like chocolate?'" Rupert spoke ominously.
"That's awful!" Betty exclaimed. "Who would do a thing like that?"
Wyllie hurriedly said, "Not me!"
"But it could be anyone," Rupert said calmly. "Simple question, gets a 'Yes' every time."
"So now that these companies have given up," Betty pursued, "do we acquire their data to demonstrate our placebo is ..."
Rupert broke in, "Not so fast! They don't always give up! Osiris is going to try Prochymal again. They want to have the first stem cell therapy on the market."
"Say wha-?" Wyllie was stunned. "For graft-vs.-host, it showed LESS response than placebo!" (See BioWorld Today, Sept. 9, 2009.)
"Oh, this is good!" cried Betty. "The plan was to push Placebolomic candidates as low-cost alternatives to overpriced drugs. But we expected low cost to be tied to somewhat lower efficacy. We may have found a path to fulfilling Obama's health care initiative for therapeutics." (See BioWorld Today, June 16, 2009.)
Rupert gleefully added, "But wait, there's more!"
Ghostwriting Without Getting Busted
Betty was always suspicious of Rupert's ideas, especially when he was so excited. "Is it legal?" she asked.
Wyllie explained, "There is a user-friendly ghostwriting program Glaxo used to promote Paxil ..."
"Called 'Casper' I presume?" Betty asked.
"Close enough," Wyllie conceded. "It was discontinued, but as far as we know it is perfectly legal. And if the ongoing congressional investigation does decide ghostwriting is illegal or unethical, we can always retract any published articles. Research fraud has led to a massive increase in retracted articles, from five in 1990 to 95 in 2008! So if any retraction we do gets buried in the heap, no one will notice."
Betty pondered this. "Something seems odd with that. Hasn't there also been a massive explosion in publications?"
"Um, yes," Wyllie conceded. "There were about 690,000 in 1990 and about 1.4 million in 2008."
"So ..." Betty punched buttons on her jewel-encrusted calculator, "it went from 7.2 x 10-4 percent all the way up to 6.8 x 10-3 percent. Of course people will notice!"
Trading Milestones for Future Sugar Pill Revenues
When CFO George Contenumbaes walked up, Betty changed the subject by asking him, "George, can you remind me of your plan to enhance revenues with our Placebolomics offerings?"
George cryptically answered, "We plan to pull a Vertex."
Rupert explained, "What he means is to do something like Vertex Pharmaceuticals: sell future milestone payments for cash now." (See BioWorld Today, July 27, 2009.)
"Didn't Enron do that with royalties?"
"Enzon," George corrected. "Yes, a couple years ago. A few others, too. But royalties can be over- or underestimated. Milestones are digital, yes or no."
"As I recall, that provides a severe dis-incentive for us to bother with the last milestone or two," Betty noted.
"True," conceded Wyllie. "If we've gotten 90 percent of the cash in hand already, that last milestone might be such a hurdle that we just don't bother.
"But who would pay us up front?" Betty asked. "And at what discount?"
"Not to worry," Rupert soothed. "Unlike other companies, we have a diversified portfolio and hence a spread risk."
"Um, aren't they all based on the same sugar pill?" Betty asked nervously.
"Yes, but spread over every indication that has ever seen a placebo effect in the clinic!" beamed Wyllie. "Plus, we also have a real drug that has excellent potential!"
Preventing a Pandemic
Wyllie smiled at the circle of puzzled expressions. "September 11 issue of Science magazine. Researchers at NYU blocked nitric oxide synthase and boosted the effectiveness of antibiotics against drug-resistant bugs. B. subtilis to B exact." (See BioWorld Today, Sept. 11, 2009.)
"So what?" asked a still puzzled Betty.Wyllie stepped back, aghast. "Why, they blocked production of nitric oxide."
Betty's long nails drummed on the wall frantically. "So. What?" she enunciated dangerously.
Wyllie gulped and spat out, "Restless third-leg syndrome! Viagra and other 'enhancers' act by enhancing production of nitric oxide. These people propose actively reversing that."
"Yes, that's how our treatment for restless third-leg works," Rupert nodded. (See "All My Clones," Episode 26.) "Are you proposing we tell our elected officials they need to take this to ward off a dangerous epidemic?"
"Such as H1N1 flu?" purred Betty. She was suddenly in a much better mood. That shopping kind of mood ... The BCBG and Mackage sample sale might be over, but there was another just around the corner.
Stay tuned for future episodes to find out:
- Blocking nitric oxide synthase can boost antibiotics efficacy for acute bouts, but the NYU researchers note chronic illnesses are another issue. So, is restless third-leg syndrome an acute or a chronic condition?
- So the BioMS trial did not pan out and their CEO and president bemoaned, "I wish it had turned out differently." Should Betty remind him of Thomas Edison's famous quote regarding large numbers of failures being a learning opportunity? Did light bulbs cost as much as clinical trials?
- Now that FDA has indicated EpiCept only needs statistical analyses supporting leukemia-free survival rather than overall survival as an endpoint, do patients in trials need to beware of falling pianos? (See BioWorld Today, Aug. 6, 2009.)
- Things seem to be going well for Betty. Isn't that the time in a soap opera when something really bad is about to happen?
Tune in next month for more "All My Clones"!
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