by Barry Werth
Smith zeroed in on the super-responders. He did a quick extrapolation, envisioning the shape of the curve. If combination therapy could dramatically boost CFTR function in even 20 percent of those sixty thousand patients worldwide with at least one copy of the delta-F508 mutation, about twelve thousand more patients might benefit from Vertex’s cocktail. “If you can take this from three thousand to fifteen thousand, that would be huge,” he suggested, brightly. Mueller, seated next to him, chafed. He reminded Smith that the study was far too small to validate any such estimate. “I would keep it as simple as we can,” Mueller said. Vertex should say the concept worked in an exploratory cohort and that the company was optimizing a final regimen before going into Phase III.
Smith persisted. He proposed emphasizing the super-responders in the press release. Olson sharply disagreed. “This says nothing,” he said.
“I agree,” Ken said.
“I also agree,” Wysenski said. “I don’t want to overstate the data.”
“The big whoopee is, even if we see with these patients what might be a billion-dollar curve, it still might be misleading, which could give a lot more patients a chance for a cure,” Mueller said. “I would leave it the way it is right now without any further interpretation.”
“The proof of concept is there,” Ken concluded. “The combo works. No one dropped out due to adverse events.”
Thus were resolved, in favor of not getting ahead of the truth, the tone and content of Kalmar’s press release, which claimed modestly that the data from the study “open the door to the possibility of treating people with the most common form of cystic fibrosis,” as Mueller was quoted saying. At the CF foundation, Bob Beall was similarly circumspect. “These data, while early, provide important new information about the potential to address the basis defect” among most patients, Beall commented.
VRTX skidded on the news. By midmorning, as the analysts weighed in and investors digested their mostly gloomy assessments, the share price plunged more than 13 percent. JP Morgan analyst Geoff Meacham, who as a PhD candidate had studied CF, expressed the majority view that the sweat chloride data were less robust than expected. “While the data are a step in the right direction, the synergy is very modest, and the data are by no means a ‘game changer,’ ” Meacham wrote in a note to clients. He questioned whether the cocktail would “materially alter the course of disease [or] its management.” Shares finished the day down 7 percent to $49.30, the largest one-day drop for the company in almost two years, erasing some of the 60 percent upsurge over the past six months.
Geoff Porges, as ever, led the bulls. He thought there was “more than enough activity to get excited.” Like Smith, he was particularly encouraged by the two super-responders, believing that further experimentation could only identify other subpopulations who, because of residual CFTR at the cell surface, would benefit from a potentiator. Even the sickest patients had some CFTR activity. This was the new world of personalized medicine: you find those individuals, by drilling deeper into their genetic makeup, who are likely to benefit most from your drug. And so even beyond the hopes and aspirations of Vertex management, Porges was utterly convinced that Vertex had already cracked open the treatment of cystic fibrosis. The combination data had to be viewed as another striking advance.
“What I say to investors is, ‘VX-770 is going to be like sunscreen for cystic fibrosis patients,’ ” he explained. “ ‘If you’ve got really light skin, you get a huge amount of benefit from sunscreen. If you’ve got dark skin, you get less benefit from suncreen. But you should all wear sunscreen if you’re going in the sun.’ If 770 only improves your CFTR function by 3X instead of 10X, that’s still better than no X. What I believe is that someday every CF patient is going to be on 770, but no one’s really thinking that. Also, when you find a treatment for a rare disease, the number of people with that rare disease gets bigger and bigger.”
Smith and Porges spoke by phone after the announcement. Ken especially was predisposed to worry about how much Smith, through his relentless courting of Wall Street, and its courting of him, could become influenced by its perspective, captivated by its assumptions, led by its needs. Porges’s excitement about the combo outdid Smith’s, but they were in close agreement that Vertex’s CF franchise offered perhaps more long-term value to the company and its stakeholders than HCV. Vertex had patent exclusivity stretching to 2025, with no competitors in sight. With patients clustered for care around a small number of specialized pulmonary centers, two dozen salespeople could cover the world. Future costs were relatively negligible. The upside was enormous.
Faced with the question of what to conclude from the study, Smith was willing to go far, but still not yet as far as the Bernstein analyst. “He wants to know,” Smith said, “why we’re not telling everybody we’ve cured CF.”
Merck made much in public of being first to get approval, as if its reps would seize an edge by reaching doctors first. Its salespeople had pressed physicians before the AdComm to begin the four-week lead-in with peg-riba early so that their patients could get on Victrelis immediately at launch. But the company planned poorly. Perhaps due to the uncertainties over its label or a more general aversion to risk taking, it decided to wait and hold its launch meeting post-launch. Instead of being out in the field, racing from practice to practice, grabbing lattes and sandwiches at Starbucks to bring to doctors, then hosting after-hours informational dinners at hotels and restaurants with KOLs for local physicians, nurses, and patient counselors, Merck’s field force was locked up in meetings. “I’ll take that week,” Cumbo said.
“That’s roughly twenty-four-hundred calls that I’ll make that they won’t. Not only that, we loaded up on programs. This week we have forty-seven satellite webinars and a hundred promotional programs. That’s just in five days. Plus I told my people to lock up all the speakers for the next week as well, so when they come out of their meeting all excited, you break their spirit.”
Emmens dismissed the turbulence in the share price. The sell-off after the release of the combo data was a “clean drop”—not caused by any troubling data. He just wanted to ensure that the stock remained high enough so that Vertex couldn’t be bought. As analysts furiously mined the first spotty weekly sales estimates compiled by the industry’s most influential monitor of pharmaceutical commercial activity—IMS Health—Emmens cautioned the ET not to put any stock in the information for at least a couple of months, when IMS assessments tend to become more credible. “We have a company to run here,” he told them.
A week after the CF disclosure meeting, Vertex bolstered its strategic position in hepatitis C by acquiring two early-stage nucs from Alios Biopharma Inc. of South San Francisco. Rather than buy the company to leverage an asset, as it did with ViroChem and VX-222, it paid $60 million up front for worldwide rights to two of the company’s preclinical hepatitis C candidates. In announcing the deal, which could be worth up to $1.5 billion to Alios if both compounds were appoved, Mueller said Vertex would begin clinical studies with the molecules in an all-oral combination with Incivek and VX-222 by the end of the year.
Emmens left early that afternoon for a forty-eight-hour blitz of Washington and New York. In DC, Sachdev toured him around the Capitol, where he met with congressmen and senators to discuss their support for government reimbursements and for screening baby boomers for hepatitis C. On a visit to NIH in Bethesda, he met for two hours with Francis Collins, its director. Collins, codiscoverer of the CF gene and a prophet of genomic medicine, was understandably pleased and fascinated with Vertex’s success with VX-770, but he was just as enthusiastic about the route the company had taken. Collins was frustrated that drug industry research productivity had declined in the past fifteen years and, as he told the Times, “it certainly doesn’t show any signs of turning around.” Earlier in the year he persuaded the White House to give NIH $1 billion to start in-house drug discovery. Whether or not the government could succeed where private industry had failed, the Obama
administration believed the problem was too serious not to try.
Emmens flew to New York and checked in at the Four Seasons on Fifty-Seventh Street, between Madison and Park. Partridge and his team had chosen the location—designed by I. M Pei; peopled by wealthy shoppers; “a remarkable luxury experience, even by New York standards,” according to its promotions—to host an investor breakfast. The next morning Emmens arrived downstairs feeling suitably refreshed. Joining him onstage, looking substantially more haggard, were Kauffman, Smith, and Fred Van Goor, the lead biologist on the CF project, who’d taken a red-eye from California. Though Incivek had scarcely been launched, Vertex wanted Wall Street to see the larger picture, and the invitation promised highlights of the company’s presentations at the just-concluded European CF meeting in Hamburg, which few of the hundred or so fund managers and analysts had attended.
“Our discussion today is about cracking the code in a complex disease,” Emmens began. “We think we’ve done this with cystic fibrosis, and that’s why there is such excitement inside the company about our recent combination data. We have Phase III results with our lead compound for a subset of patients with this disease. These results are dramatically positive. We think we can apply what we know about the science underlying the disease to be able to help many more patients. That’s a very big deal and that’s an underappreciated opportunity.
“We don’t have all the clinical data to prove this yet, but we’re in a unique position to proceed. We’ve cracked the code and we’re spinning the dials. We have the stethoscopes out and we’re listening to the clicks. We believe it’s a matter of time before we break this disease wide open and make a really big difference for a lot of people.
“From a business perspective CF is a very traceable and tractable market for a company that wants to stay, as we do, lean and very efficient commercially. CF treatment is concentrated among specialists. It requires a very small commercial footprint to reach patients with CF and the people who care for them. In fact we don’t call sales forces like that salespeople. We call them enablers. The scientific core of our company is making a difference in the treatment of serious diseases like CF and hepatitis C, and these turn out to be disease opportunities where reimbursement is more favorable, where you don’t need to build and maintain a large sales force, and you can build a global operation in a relatively straightforward manner. That’s how we think about building our business.”
He turned over the microphone to Dr. Susanna McColley, head of the pediatric cystic fibrosis center at Children’s Memorial Hospital in Chicago. Dressed in a tapered white knit suit with black buttons, a gold chain necklace, and stiletto heels, McColley introduced her slide show with a personal anecdote. She had decided as a post-doc at Johns Hopkins in the early 1980s that she wanted to do clinical research in CF. Her advisor at the time told her there was no such field. Since the gene was discovered, she’d watched her patients suffer and die amid fading hopes for a cure. After detailing the VX-770 Phase III findings, McColley said: “This is truly the most exciting clinical trial data I have seen. I’m not trying to be hyperbolic here. I don’t have a financial relationship with this company. But after twenty-two years waiting for something, with all these promises made back in 1989, it’s very exciting.”
McColley said little about the combination data, which remained preliminary. But she discussed findings from the just-concluded DISCOVER study of VX-770 in patients with two copies of the delta-F508 folding defect—Keith Johnson’s trial. “There was not a clinical benefit of VX-770 as monotherapy in this group,” she reported, explaining:
“I want to stress again you wouldn’t expect to see that, because of the way this mutation works. There were some patients, though, who did have a pretty big drop in sweat chloride. This is likely due to the fact that there is an occasional delta-F508 CFTR protein that winds up on the cell membrane. That’s speculative. But this supports going ahead with the studies combining 809 and 770.”
Smith invited questions. In answer to a wandering query from Morgan’s Geoff Meacham about the combo data that seemed more likely to impress his clients than to elicit new information, Kauffman reprised McColley’s message that Vertex was steaming ahead. “We want to maximize the correction so we can get as much CFTR on the surface as possible and then add 770 on top,” Kauffman said. “If we can do that we’re gonna see a more dramatic effect than we’ve seen here.”
Meacham followed up. “Did you harvest any bronchial epithelial cells from patients?”
“You can’t really do that on living people,” Kauffman said.
McColley had watched her patients’ life expectancy triple in thirty years, but she had “just lost an eleven-year-old,” she explained, indicating that there remained much more to be done. An investor asked if she had any G551D patients for whom she wouldn’t prescribe Vertex’s drug. “The pressure on clinicians is going to be with the zero-to-six-year-olds,” she said. “One hundred percent of US states, a lot of the EU, Washington DC—all have newborn screening now. So we’re identifying this mutation by four weeks of age. The pressure is going to be: ‘Can’t we crush the pill and give it to our baby and won’t that prevent her from developing CF lung disease?’ The answer to that question is, ‘Quite possibly, yes.’ But first you need safety, pharmacokinetics, etc. I can’t really in good conscience give a drug to a young group of patients for whom it hasn’t yet been studied.”
“Just to comment,” Kauffman inserted, “we’re designing a study now beginning in infancy to cover the age range three months up to six years. It’s in process.”
“It’ll never be fast enough for my families. I just want you to appreciate that,” McColley said.
“I understand.”
Smith left five minutes at the end for discussing the launch of Incivek, about which the company had scarcely more granularity than the analysts. He invited questions, but before anyone could raise a hand, Emmens jokingly piped up, “How’s the launch going?” There was uncertain laughter. They knew he couldn’t really comment: Reg FD restrictions, for one thing; lack of real data, for another. “Sorry,” he said, “I couldn’t help it.”
“How is the launch going?” Smith asked.
“This my sixteenth drug launch in my career,” Emmens answered. “That means I’m old.
“There’s two ways to look at it. One is, you’re gonna look at prescriptions, and you’re gonna look at them too soon, and you’re gonna project too much. What I tell you is I listen to the sales force noise and the feedback that we get. They go out at one hundred ten percent. How long that stays is a very good indicator. If that’s not there, there’s something wrong.
“There’s nothing wrong. We’re getting great feedback. That’s all we can say at this early stage. It’s going great.”
Keith Johnson got a phone call that Monday from the codirector of the cystic fibrosis center in the department of pediatrics and pulmonary medicine at Beth Israel hospital, Dr. Maria Berdella. He was at the W hotel in Union Square on business. “She said, ‘They’ve terminated the study,’ ” he recalls.
“She said, ‘Look, I know you’ve done really well on this med, but they say it’s not meeting their end points. They’re just terminating the study.’ I said, ‘What do you mean, terminating the study? What do you mean, not hitting their end points? Why take it away from me?’ I thought I was on it forever. It would be FDA approved, and somehow we would find a way to get it. I thought somebody somewhere would look at this and say, ‘Okay, this guy gets the drug.’ Somebody would be my advocate. There would be a mechanism in place, because why wouldn’t you want this for a patient?”
Ken had anticipated the disappointment facing Johnson and others who had rolled over in the study, and he was “really ripped about the way we’re talking about it” inside the company. Smith wanted to disclose that almost a third of the patients rolled over, suggesting a robust response to the drug. But Ken worried that the criteria used in determining who got to stay on the drug afte
r the initial evaluation period were badly designed and thus the data would ignite false hopes. Subjects in the first part of the trial qualified for the open label extension based on either a 10 percent actual rise in FEV1 or a 10 percent drop in sweat chloride—at any single point in the study. “You could have been twenty points below at the end of the study, but if you had a spike up ten points during the study you got rolled over,” Ken observed. Sweat chloride can’t be influenced by other factors. But FEV1 “is not exactly a precise measurement,” as he explained. “You have these spikes on a regular basis.
“As proof of that, we had a significant number of placebo group people who qualified for the rollover—because of an FEV1 spike. We have a whole bunch of people in that group and I had to fight to make sure that we were not going to disclose any of that, because I thought the disclosure was misleading. It turns out that we have now disclosed that we’ve terminated that rollover group—because it’s not having any effect. In other words, exactly what I was worried about becoming the reality. So I want to get that information out. I pushed to have that released because I want doctors to know that at least that little bit of data that we have says it doesn’t work.”
Ken feared that Vertex faced a dangerous dilemma if there was any ambiguity about whether 770 alone could benefit patients with two copies of the DelF508 defect. Despite persuasive preclinical evidence that the drug could be effective in people with other gating mutations, the FDA, moving cautiously, had indicated it was likely to approve it only for the 4 percent with G551D. With such a narrow label, the looming question of what physicians and payers would do regarding the other 96 percent once VX-770 was approved weighed heavily on the company.