There are many ways to fail in the pharmaceutical industry. Between all the research and clinical trials, new drugs have timelines and standards to adhere to, and there are lots of things that can go wrong. Most of the failures can be grouped into either bad science or bad business. On June 18th, Dr. Casey Cunningham, Chief Scientific Officer of Santé Ventures, came to Platform Houston to talk about drugs failing because of bad business.
Cunningham began with a hypothetical example sprinkled with actual experiences that he’s had. In what he called “a very typical opportunity that we see,” a scientist analyzing gene expression patterns and cancer stem cells finds a particularly activating pathway, and then finds someone with a good high screening system. The scientist successfully finds one signaling pathway, which goes through more testing and structure analysis. The scientist gets a hold of a chemist, and she performs breast, colon, and prostate cell line studies. Synogram studies show remarkable results, the scientist collaborates with a colleague of hers on orthotopic models, which lead to published papers that form the basis of a grant.
When the scientist and chemist find a parallel signaling pathway that is independently regulated, they meet up with a colleague in that area to combine the two for non cross-resistant molecules. They have the idea to form a company, and they plan the necessary trials.
They meet a multiple myeloma expert based in Australia, do cheaper clinical trials there, meet with key opinion leaders in the solid tumor sites, appoint management to the company, raise angel funding, pitch the drug to venture capitalists, and think they’ll get traction.
However, the drug will fail.
Why? Because the company is going to fail, Cunningham said. As a disclaimer, Cunningham said that nothing he was saying was “iron-clad, 100% true.”
Science plays a very minor part – 10% – in a drug’s success, according to Cunningham. “The original discovery is only a fraction of the overall value.”
The first lesson Cunningham said he learned working on the “other side of the bench” was that the science of failed drugs is usually good.
“I spend my days looking at opportunities,” Cunningham said. “The number of opportunities that I was able to categorically reject as bad science I can probably count on the fingers of both hands. Most of the time, the science seems fine. You can’t argue with the science. Now, those who are basic researchers can often find small nuances where you question this conclusion or that conclusion. But the overall [question] – is this a potentially useful pathway – is nearly always true.”
Cunningham also said that when academic researchers start out, they think – as he once thought – that science is everything.
“[They think] that its the discovery that’s the value, the rest is engineering. They also have an exaggerated sense of how much this is worth at this stage, and how much of it they should own, because they’re the discoverers,” Cunningham said. “And I repeat, most of the time, the vast majority of the time, it’s not the science that’s the problem.”
Patients, Cunningham said, are not the final customers in the pharmaceutical industry. The final customer is the acquirer of the drug.
“Most patients aren’t taken care of in academia,” Cunningham said. “The vast majority of patients get treatment in community settings under different sorts of guidelines. Now, that difference has narrowed since I was training. It used to be that in academia, you had a fair amount of freedom as to how you could treat patients – community doctors did too. And then things like clinical practice guidelines begin to emerge, as reimbursement became tied to SOPs [Standard Operating Procedures], so you no longer quite had the freedom of prescribing or using drugs at different stages, you had to follow certain established guidelines. That’s not actually coming from academia… but there is still sort of a lack of recognition that that is what drives, many treatments, at least initially.”
According to Cunningham, researchers have to start at the end when developing a drug – meaning, they have to keep the drug acquirers in mind.
“If you think about it, you’re not actually developing a drug to treat cancer, or even colon cancer or breast cancer,” Cunningham said, directing the audience to look at the label of drug Synribo on the screen.
“Read the key phrase – it’s for treating chronic myeloid leukemia in adult patients with resistance or intolerance to two or more tyrosine kinase inhibitors,” Cunningham said. “It’s very specific where this drug is actually approved for, if that’s its label indication.”
Cunningham said that in the old days, pharmaceutical companies would find some label indication that gave them the fastest path towards approval, and then figured the doctors would use it anyways.
However, that’s becoming increasingly difficult. with clinical practice guidelines.
“Now a pharmaceutical company has to play a lot more attention to what its final label indication is going to be,” Cunningham said.
This makes the phase 3 – which is the most important phase regardless – always of the trial way more important than the phase 2, and certainly more important than the phase 1, according to Cunningham. Additionally, early phase trials need to set up for the phase 3, so that it can achieve approval for the label indication a pharmaceutical company wants.
According to Cunningham, researchers regard drug development as a science project, which can divert them from the end goal.
“So even getting to clinical trials are an attempt to enlarge understanding of the biology, so [they] design their early phase trials to test whether or not the drug has activity in these pathways, which are important to these tumors, and also respond to that tumor. When you think of it that way – and it’s a perfectly fine way to think of it – you get led of into – not traps, but pathways that aren’t actually the end goal,” Cunningham said.
Furthermore, Cunningham said that risk is not an additive. It’s multiplied, he said, referencing his hypothetical example.
“Remember, the powerhouse combination is two drugs for these parallel pathways,” Cunningham said. “Both of those were experimental drugs. That’s exceedingly difficult to do through a regulatory pathway anyway, and you just multiply the risk of things like manufacturing and formulation.”
Cunningham said time is money, and not just in the usual sense – it’s called the burn rate for a reason.
“The thing I tell my scientific buddies as they form a company is, ‘everyday you’re going to bring a sack of $50 dollar bills, and dump it on the middle of the table and set fire to it,” Cunningham said. “You assign somebody to figuratively do that everyday. Now, that informs your decisions, because as scientists, we go back and forth. Sometimes, we want to do the most thorough investigation, sometimes we want to do the most elegant investigation. As a scientist, you’re thinking in terms of grants – time sort of doesn’t matter, a lot of the sequencing doesn’t really matter. But in a company, burn rate is the killer – [for example] six months of formulation work to improve solubility.”
Cunningham said that at least in his journey, he’s learned about the things that can go wrong that didn’t have anything to do with what happens in the lab. However, good drugs are still made. There has been a tremendous amount of progress, particularly in oncology.
“We’re looking for something that makes a 40% difference with one drug, Cunningham said. “We ignore the fact that for the past 10 years, there’s been a 4% difference each year.”
One of the reasons we think that things are not on deadline is because these accomplishments are not done in a headline-generating way.
“There is still hope,” Cunningham said.