Combination therapy: Back to future or wave of future?

04 Dec Combination therapy: Back to future or wave of future?

When I started in the pharmaceutical industry eons ago, the trend in the United States and the Food and Drug Administration was for single drug approval. This trend bucked what was happening in other parts of the world where a drug often consisted of what would be considered multiple drugs today in the U.S.
For example, an antibiotic for respiratory disease would also contain anti-inflammatory agents, analgesics and vitamins. The concern in the U.S. and the FDA at that time (and still today) is what’s called “drug-to-drug interactions.” This phrase means that when you add drug “A” to drug “B,” you potentially trigger additional adverse side effects that could negatively impact the patient.
By the way, this is not just limited to drugs but to certain foods as well such as grapefruit, which potentiates such drugs as antihypertensives (for combating high blood pressure) and hypercholesterolemia (for combating high cholesterol).
In Latin America, Asia and Africa, this multi-drug regimen in one combination drug went more than a bit overboard as strange arrays of combinations often appeared. The rationale in those countries for approving such strange and often overloaded combinations was that the local regulatory authority already approved the individual drugs.
Not much care was taken to look at the potential for inter-drug reactions.
As we get older, the reality is that we tend to take more medicines – sometimes three or four different ones a day – to manage a number of diseases including arthritis, hypertension and diabetes. Each medicine has its own dosage regimen. This often makes it difficult for the patient to remember the correct schedule for all the medications.
This situation leads to a lack of medication compliance. This means the patient is not completing the correct medication schedule and isn’t correctly treating his or her own disease.
U.S. vs. international
For years, the trend in the U.S. has been to buck this international combination drug regimen because of the great concern about the lack of data on a large scale to show the interactivity of drugs when combined. The reality is that the FDA is also aware of this compliance issue and patients are often taking multiple drugs at one swallow or during the day.
In my earlier days, I didn’t really take much notice of this trend as I rarely ingested any drugs. As I have gotten older and increased beyond just the occasional aspirin to regular medication, I often have wondered why Big Pharma or even “New Pharma” haven’t been more aggressive about combining drugs and making life (and treatment compliance) easier for patients.
The reality is that both Big Pharma and even some newer specialty pharma companies have woken up to this idea (as has the FDA). This awakening, though, is not necessarily for the above reasons.
Here’s a case in point: Pfizer has two drugs – Norvasc (an antihypertensive) and Lipitor (a drug for high cholesterol) – and both of these drugs are either off patent in some parts of the world or are going off patent in the near future. Pfizer has combined them into one new branded drug called Caduet. While I’m not aware if this combination allowed Pfizer to seek new additional patents on the combination, the reality is that:
1. This combination does make life simpler as many patients with high blood pressure also have high cholesterol.
2. These two drugs are both leaders around the world in terms of annual sales and together represent for Pfizer about $18 billion a year. Both drugs are losing patent exclusivity.
3. Pfizer is seeking a way to protect this revenue and profit franchise.
4. These drugs are probably already being used together by patients.
Another different type of combination on the market (but also in the cardiovascular disease area) is the combination of two different drugs for one disease: high cholesterol. Merck has combined one drug (a statin agent) with another anticholesterol drug from Schering-Plough that has a totally different mechanism of action to try to increase the overall impact of scrubbing out cholesterol from the blood.
Statin agents have been a very powerful addition to the efforts to reduce cholesterol. However, they have at least one major drawback: the impact on the liver (they increase liver enzyme activity). This means they are putting the liver to work on a higher level, which isn’t necessarily good.
If you can reduce the amount of the statin drug by combining it with another drug that works in a different way, you are in essence providing the patient with more drug efficacy with less drug side effects.
Now I’m sure some of you are going to say this approach isn’t new and has been used for 30 or more years and approved by the FDA. My response to that is it’s true. A number of cardiovascular drugs have been combined with other types of cardiovascular drugs for some time including vasodilators with diuretics and beta blockers with diuretics.
There are other classes of drugs where combinations have been approved such as HIV therapy (where it is known that “cocktails” of drugs with different mechanisms of action are critical to halting the disease progress). Abbott has been very effective in combining HIV drugs. This helps patient compliance, enhances therapy and protects Abbott from losing part of its franchise as a result of patent expirations.
There are even situations where the FDA has allowed the pre-packaging of already approved drugs to treat a disease (such as peptic ulcer). Cancer drugs, which are also given in drug cocktails in a hospital setting for a similar reason as HIV therapy, are usually pre-mixed in the hospital in infusion bags.
It may well be that approved combinations are in essence approved by the FDA in the near future. Today, they are in that gray zone that allows doctors and pharmacists to compound (read: “mix”) medicines in a pharmacy or hospital setting.
The Baby Boomer impact
The driving need to simplify drug administration to patients (and thereby enhance patient compliance to treatment) is a powerful incentive for companies and the FDA to approve more combination therapy. I think we will see more and more of such combination therapy particularly as the baby boomers start aging into their late 60s and 70s and require more and more medications.
Abbott has already been proactive in this area when they in 2006 acquired a cardiovascular specialty pharma company (Kos Pharmaceuticals) for $3.7 billion.
Its key product was a drug actively used in lowering cholesterol that can be combined with other cholesterol-lowering agents. Abbott and Kos have looked at combining this drug with a number of other drugs including a three-way combination with AstraZeneca’s Crestor.
During the 1990s, the rush by Big Pharma to enhance patient compliance was going from regular dosage release to controlled release (i.e. taking a pull just once a day instead of four times a day). This mechanism allowed for better patient compliance and also afforded some additional patent protection and product life.
During this decade and the next, the trend to further enhance patient compliance and drug patent life will be combination drug therapy. Though I have not seen the full financial impact on the market of this trend, it’s clearly one way to avoid rapid product sales deterioration when a drug loses patent exclusivity. This also clearly benefits the patient.
I only hope that Big Pharma will be smart enough to make these combined drugs in easy-to-swallow forms and not in big mega pills. Such forms could include liquids, gel caps, patches and even nasal sprays. See you soon!
Previous articles by Michael Rosen
• Michael Rosen: Angel investing slows during first half of 2007
• Michael Rosen: University research and life science collaborations drive new approaches to disease
• Michael Rosen: The ease of biotech beyond the Midwest and the U.S.
• Michael Rosen: Japanese biotech: A Midwestern perspective
• Michael Rosen: The cost of doing biotech business: Midwest cheaper than the coast, but not by much?