Therapeutic Focus: Cardiovascular
The cardiovascular space has long ranked among the pharma industry's most vibrant. Even by that standard, however, 2015 is shaping up as a blockbuster year, and PCSK9 inhibitors have a lot to do with projections. Estimates for their success could prove even better if they are shown to reduce cardiovascular event risk, as well. Joe Dysart explains
Breakthroughs in cardiovascular research are promising to pump up profits in the sector, as a slate of in-development drugs are being readied for rollout during the next few years. And the major winner could be Merck, whose drug Vytorin significantly reduces the risk of a cardiovascular event, according to study results released in November.
Other potential winners include the developers of PCSK9 inhibitors—extremely effective cholesterol-lowering drugs designed for the estimated 20% of patients who cannot stomach statins, the current treatment standard for lowering cholesterol. Still other victors could be makers of blood thinners, who have secured a number of industry-favorable rulings from the FDA over the course of the past year.
In the short term, the drug that could make the biggest splash in the cardiovascular sector is Vytorin. Results from the IMPROVE-IT study released last November found that patients taking Vytorin experienced a 6.4% reduced risk of cardiovascular event. (See related story, here.)
“The study is the first to show that adding a non-statin drug [Zetia] to a statin [Zocor] to improve cholesterol levels can help patients with specific heart problems do better,” states Christopher Cannon, lead author of the study and a professor of medicine at Harvard Medical School and physician at Brigham and Women's Hospital.
Lori Mosca, a professor of medicine at Columbia University Medical Center and director of preventive cardiology at NewYork-Presbyterian Hospital, agrees. “These study results will help expand our treatment options for high-risk ACS patients, especially among those who are intolerant of or who do not achieve desired results with intense statin therapy,” she states.
The IMPROVE-IT study also found that Vytorin users not only lowered their risk of heart attack by 14% but also lowered their risk of ischemic stroke by 21%, according to Cannon.
All told, the cheery results could spike Merck's revenues by as much as $500 million annually once the drug's label is updated to reflect the data, according to Leon Henderson-MacLennan, a medical adviser at inThought Research Group. But the possibility of all that froth comes with one big caveat. “In order to get to these lofty goals, we have to do a heck of a lot better in terms of compliance rates, in the first place,” he tells MM&M. “We already lag in that regard.”
A Morningstar analysis released in October with respect to Vytorin was also guardedly optimistic. It anticipated that the IMPROVE-IT study would spike sales “slightly” for Vytorin in 2015 as well as in 2016. That analysis notes, however, that the drug will be exposed to generic competition by 2017, which will most likely further dilute the impact of the IMPROVE-IT study.
Meanwhile, similar hopes for sales spikes are pinned on a new class of drugs designed to reduce cholesterol for patients who cannot take statins: PCSK9 inhibitors. These drugs, which block the PCSK9 protein, have reduced LDL cholesterol counts to as low as 25mg/dL in clinical tests. They are currently being developed by a number of big players, including Amgen, Pfizer and the team of Sanofi and Regeneron.
The drugs could provide relief to as many as 20% of patients who are statin-intolerant—that is, to patients who have experienced side effects like muscle fatigue and impaired cognition, according to research at The Rockefeller University.
A Jefferies survey released in March predicted that sales of PCSK9 inhibitors could hit $5 billion annually when they eventually do reach the market. But once again, Henderson-MacLennan sounds a cautious if not overtly skeptical note. He believes that that kind of sales volume is possible, but only if patients actually buy and take the PCSK9s that their doctors prescribe for them. “I think that the PCSK9s will prove welcome additions to the armamentarium,” he says.
Battling to bring the first PCSK9 to market are partners Sanofi and Regeneron, who brought back stunning results from six Phase-III trials of their PCSK9, alirocumab. Those results were released at the American Heart Association Scientific Sessions in November. In clinical trials, more than 500 patients achieved LDL cholesterol levels lower than 25mg/dL, according to Jennifer Robinson, director of the prevention intervention center and a professor in the departments of epidemiology and medicine at the University of Iowa's College of Public Health.
Sanofi and Regeneron spokesmen say that they planned to have submitted alirocumab for licensing by the FDA and European agencies before the close of 2014. They were also planning to fast-track the review process in the US by employing a Priority Review voucher that they had purchased from BioMarin for $67.5 million. A Morningstar analysis released in November describes the initial data on alirocumab as “strong,” which Morningstar says should give the Sanofi and Regeneron partners added pricing power and market penetration.
Meanwhile, competitor Amgen has its own PCSK9—evolocumab—which is already up for licensing review in Europe and the US. Amgen says that it is banking on a favorable US decision by August of this year. The Morningstar analysis estimates peak sales at $5 billion.
One of the factors behind such optimistic sales projections for the PCSK9s is that test results have been so head-turning that cardiologists are already primed to start prescribing the drugs. Indeed, a Jefferies survey of 50 cardiologists in 2014 found that those doctors are ready to incorporate the unproven PCSK9s into their standards of care for high-risk patients.
Specifically, the Jefferies survey indicated that doctors expected to prescribe PCSK9s to 10% to 23% of their high-risk patients before cardiovascular outcome data is even tallied. These estimates would rise to 29% to 37% of patients if the drugs were shown to have a cardiovascular benefit.
Other potential shifts in the cardiovascular market to monitor include one from AstraZeneca, which won FDA licensing for its lipid-regulator Epanova this past year, and another from Merck, which won approval for its thrombotic cardiovascular event reducer, Zontivity.
“This approval is a significant milestone for AstraZeneca, as it strengthens our existing portfolio of cardiovascular medicines,” states Briggs Morrison, EVP, global medicines development and chief medical officer at AstraZeneca.
Eugene Braunwald, a physician who has studied Zontivity, adds that “a new treatment option like Zontivity is an important advance that can help to lower that risk for appropriate patients taking aspirin or clopidogrel or both.”
Les Funtleyder, healthcare portfolio manager at E Squared, likes yet another heart drug, LCZ696. It's currently under development at Novartis and is designed to slow cardiac decline for patients suffering from chronic heart failure. LCZ696 reduced the risk of sudden cardiovascular death by 20% compared to those who took enalapril, in a Phase-III trial. “I'm excited about Novartis's new heart-failure drug LCZ696,” Funtleyder says.
Meanwhile, blood-thinner makers have been securing a number of favorable FDA and other federal agency rulings during the past year, readying the market for growth this year. AstraZeneca, for example, was cleared of allegations by the US Department of Justice last summer that it attempted to tamper with test data results for its anti-platelet drug Brilinta.
“We have always had absolute confidence in the integrity of the PLATO trial and we are proud of the important benefit Brilinta offers to patients around the world,” states AZ CEO Pascal Soriot.
Even so, Funtleyder believes that the exuberance over the ruling could be short-lived. “I don't see Brilinta increasing much, as there is generic competition,” he notes.
Meanwhile, partners Bristol-Myers Squibb and Pfizer received a boost for their anticoagulant Eliquis with a number of new-use approvals. Last March, a new market for the drug was opened when the FDA approved the use of Eliquis to reduce the risk of blood clots in patients who have undergone hip- or knee-replacement surgery. Additionally, Eliquis was approved by the FDA for use as an anticlotting treatment for deep-vein thrombosis and pulmonary embolism, a move interpreted by Zacks Equity Research as a “huge positive” for the drug's sales. Yet another use for the drug—for the treatment of DVT and PE—was approved in Europe.
All told, all the additional uses helped spike year-over-year sales of Eliquis for the third quarter of 2014 to $175 million. “We achieved significant progress in our pipeline and saw strong in-market performance for key products including Eliquis,” says BMS CEO Lamberto Andreotti. Indeed, the Morningstar analysis describes Eliquis as a “likely blockbuster,” which is aided by “one of the most powerful sales forces in the world.”
Another pair of new-use winners were Bayer and Janssen Pharmaceuticals, which secured an additional use for anticoagulant Xarelto from the FDA. It was approved to reduce the risk of stroke and systemic embolism. The approval offers patients “a new option to reduce stroke risk,” states Gerald Naccarelli, chief of the division of cardiology at Penn State's College of Medicine.
A final encouraging FDA ruling went Boehringer Ingelheim's way. The FDA found in October that BI's anticoagulant Pradaxa significantly reduces the risk of stroke and intracranial bleeding. Additionally, Pradaxa turned in a 14% better survival rate than warfarin. Overall, the study confirmed that Pradaxa's hoped-for benefits were documented in “real world general practice,” according to JЪrg Kreuzer, vice president of BI's medicine therapeutic area cardiovascular.
Adds Funtleyder: “On Eliquis and the factor Xa class like Xarelto and Pradaxa, they probably gain share due to the move away from warfarin rather than because of label expansions.” And why is that important? “Warfarin is one of the top causes of drug-related hospitalizations,” he explains, “so the sooner we can improve on that, the better.”
Next page: Clinical Corner—Neutralizing the chances of a blood-thinner-using patient bleeding out after traumatic injury or during emergency surgery
Clinical researchers may soon be neutralizing one of the unfortunate trade-offs associated with oral anticoagulants (OACs): the danger of a blood-thinner-using patient bleeding out after traumatic injury or during emergency surgery. At least three drugmakers are closing in on blood-thinner antidotes, which appear to quickly restore the blood's inherent ability to coagulate.
Boehringer Ingelheim, for example, released study results last November documenting that its antidote for its blood thinner Pradaxa, idarucizumab, successfully reversed the effects of Pradaxa in 35 patients. “These data are the first to show idarucizumab reverses dabigatran-induced inhibition of wound-site fibrin formation, which plays a key role in the blood-clotting mechanism,” states Joanne van Ryn, who works in BI's department of cardiometabolic disease research.
Researchers viewed the BI study results as extremely promising, given that the antidote was well tolerated by patients and did not cause any clinically relevant side effects, according to Jörg Kreuzer, a vice president in BI's medicine therapeutic area cardiovascular. “The specific investigational antidote for Pradaxa, which our scientists at Boehringer Ingelheim are developing, would give physicians an additional and highly targeted option beyond the already-existing measures for treatment in clinical situations where patients might benefit from an immediate reversal of the anticoagulant effect of dabigatran.
BI's antidote has been on the radar of FDA regulators since June, when the company scored a coveted Breakthrough Therapy designation from the agency. A global Phase-III study of the drug—RE-VERSE AD, short for “reversal of Dabigatran anticoagulant effect”—was green-lighted at BI last May. Twenty-nine countries are already involved in the study and BI is looking to add another six.
Meanwhile, drugmaker Perosphere is posting similarly encouraging results for an antidote it is currently researching for OAC edoxaban, which is in development at Daiichi Sankyo. Phase-I/II study results released last November by Perosphere show that a single 100- to 300-mg dose of its antidote PER977 restored hemostasis from the anticoagulated state induced by Daiichi Sankyo's blood thinner.
“The fact that PER977 was shown to be safe, well-tolerated and, most importantly, effective in reversing edoxaban, one of the new factor Xa oral anticoagulants, is a major step forward,” states Dr. Jack Ansell, former chairman of the department of medicine at Lenox Hill Hospital, in New York City, and a scientific adviser to Perosphere. Even more promising results in blood-thinner reversal were released in November by drugmaker Portola. The company has been working on an antidote for factor Xa inhibitor blood thinners made by Daiichi Sankyo, partners Bristol-Myers Squibb and Pfizer, and partners Bayer HealthCare and Janssen Pharmaceuticals.
Phase-III clinical trial results released by Portola in November revealed that its in-development antidote, andexanet alfa, produced a 94% reversal of the effect of Eliquis in health volunteers aged from 50 to 75. “We believe andexanet alfa could be the first universal Factor Xa inhibitor antidote available for anticoagulated patients who are experiencing a major bleeding event or those needing emergency surgery,” says John Curnutte, executive vice president, research and development, for Portola.
Eliquis tops Rx cardio brands onlineEliquis (apixaban), the oral anticoagulant sold by Pfizer and Bristol-Myers Squibb, drew the highest ranking among CV brands by cardiologists in terms of online presence, according to a study fielded in third-quarter 2014 by Digital Insights Group (DIG).
“Cardiologists have always embraced the digital angle,” says Mark Bard, CEO of DIG. “Web-based branded communications are very relevant given how important drugs are to the treatment plan. Eliquis has done a good job the last six months.”
As have Daiichi Sankyo/Eli Lilly's Effient, Actavis's Bystolic, Pfizer's Lipitor and J&J's Xarelto—they rounded out the top five online Rx cardio brands. DIG asked the 200 or so physician respondents to rate brands on several metrics, including overall quality of branded content and accessibility across devices. The latter refers to whether the sites are mobile-optimized and feature responsive design.
Eliquis also garnered the highest share among products in its class in terms of traffic to its sites by mobile device. The warfarin-replacement drug, approved by the FDA in 2012 for stroke prevention in patients with atrial fibrillation (SPAF), has since picked up additional indications, and Pfizer/BMS have revamped their commercial strategy.
“Increasingly we're seeing the value of co-pay and loyalty programs,” adds Bard. “It's relevant to cardiology and things like immunology. It's not just clinical but also providing something a patient could use.”