The Perils of R&D in Well-Trodden Areas
To most working in pharmaceutical R&D, it became clear a decade ago that the era of novel anti-hypertensive research was coming to a close. The blood pressure market was saturated with many safe and effective drugs, most of which were generic or soon to be so. These treatments included diuretics, beta blockers, alpha blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Thus, it was pretty surprising that Novartis pursued renin inhibition, yet another type of mechanism for blood pressure lowering. This approach was not novel. In fact, scientists had been working on trying to discover and develop novel renin inhibitors since the early 1980s. For a variety of reasons, most companies had abandoned their efforts by 2000 as it was no longer clear that a renin inhibitor would have any benefit over existing therapies.
Thus, it was pretty surprising that Novartis continued in this field and brought aliskerin (sold as Tekturna or Rasilez) to market in 2007. The fact that Novartis scientists were able to find such an agent after decades of research in an area where many had failed was remarkable. Aliskerin was indeed a potent blood pressure lower. It significantly lowered blood pressure for a full 24 hours when given as a single dose and added efficacy when dosed on top of other blood pressure medications. But its blood pressure lowering effects weren’t dramatically better than existing therapies. Was aliskerin too late to market for it to be a commercial success? Renin is an enzyme that initiates the first step in what is called the “renin-angiotensin (RAS) cascade” that ultimately produces the blood pressure regulating peptide angiotensin 2. But the ACE inhibitors and ARBs both also target the RAS cascade, so many questioned whether aliskerin would offer meaningful advantages over existing agents. Why would payers be willing to pay a premium price for a new unproven agent without superiority data?
Novartis tried to show the medical importance of aliskerin by conducting a number of long-term outcomes studies to demonstrate its advantages. One of these was called ALTITUDE (ALiskerin Trial In Type 2 Diabetics nEphropathy). Novartis described the trial as follows:
“The placebo-controlled Phase 3 ALTITUDE study is the first trial to investigate Rasilez/Tekturna for more than one year in a specific population of patients with type 2 diabetes and renal impairment. These patients are known to be at high risk of cardiovascular and renal events. In the study, Rasilez/Tekturna was given in addition to optimal cardiovascular treatment including an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).”
ALTITUDE was an events driven study involving 8,600 patients and it was monitored by an independent Data Safety Monitoring Board (DSMB). Novartis was hoping to show that aliskerin, when added to conventional therapy, delayed heart and kidney complications in the type 2 diabetes population. Basically, Novartis hoped that in addition to lowering blood pressure aliskerin would also have protective effects for organs like the kidney. In studies like this, it is the role of the DSMB to monitor the progress of patients on a periodic basis in order to determine how well the novel treatment is working.
On December 20, Novartis announced that the DSMB recommended that the ALTITUDE study be halted. To great surprise, they found that the trial arm that contained aliskerin after 18 – 24 months resulted in an INCREASED incidence of non-fatal stokes, renal complications, hyperkalemia and hypotension in this high risk study population. As a result, Novartis immediately halted promotion of aliskerin-based products for use in combination with ACE inhibitors or ARBs. For some unknown reason, aliskerin doesn’t seem to have organ protective properties, but its use appears to cause unforeseen toxicities when given in combination with other blood pressure lowering medications.
This is a terrible result for Novartis and is likely to cause the demise of this drug. Matthew Herper’s Forbes story on this event contained the following quote from Texas cardiologist Dr. John Osborne, who summarizes the situation that Novartis now faces:
“The Novartis hypertension franchise is now DOA, obviously. Furthermore, this class of DRIs has died with the death of this drug… Furthermore, given this data, why would one use this molecule anyway?”
A few lessons can be drawn from this.
1) Going after a new mechanism where there are already excellent treatments on the market is always very risky, especially when generics are already present or on the horizon. This isn’t limited to anti-hypertensives. For example, an area like LDL-cholesterol lowering is very well-served with statins. Any new LDL-lowering agent would have to be very special for payers and physicians to accept it. The same thing can be said for anti-histamines, anti-ulcer agents, etc. R&D resources are best spent in areas of major medical need, where a new medicine can make a difference.
2) If you still believe your new drug has something to offer patients, despite the fact that good medicines already exist in this therapeutic area, it behooves you to do key clinical studies before filing the NDA. My guess is that, despite the fact that Novartis has generated income over the past 4 years with aliskerin, the R&D, manufacturing and launch costs for this drug were pretty high and not compensated for the sales to date.
3) This type of result further supports conservatism by regulatory authorities. I wouldn’t be surprised if the FDA uses this case as an example of why they want more Phase 3 studies carried out BEFORE approval in order to justify registration of a new drug in a therapeutic area already well served.
When a drug fails, it is not an event that impacts only one company. Presumably, other R&D organizations will learn from this and design future clinical development programs appropriately. For regulatory agencies, one would hope that this type of result won’t cause further conservatism and cause them to increase the demands placed upon companies charged with the discovery and development of new medicines. Finally, this is another example that can be used to teach the critics of the drug industry that the work pharma does is challenging and highly risky – yet important to the health of us all.