Me-Too Drugs – Innovation Killers or Backbone of Drug Discovery?

copycat identical white windows

‘Me-too’ or ‘follow-on’ drugs are the copycats of the drug discovery landscape. Taking inspiration from existing drugs and making small modifications to them, many new therapies have been developed in this manner. Despite their reputation for lacking novelty and innovation, the sheer success of me-too drugs, like the blockbuster drug Lipitor, makes them the backbone of many medicinal chemistry programs.

What’s a ‘Me-Too’ Drug?

Scientific advancement is built upon past knowledge. The successes (and failures) of generations of scientists shape the way we understand the world today. This is also true in medicinal chemistry, where new drugs are always being developed to improve upon existing versions. Although there isn’t a set criterion as to what constitutes a me-too drug, they are loosely defined as drugs of the same class with similar effects and structure.



Me-Too Strategy in Drug Design

Me-too drugs take this mimicry to another level by copying the basic chemical structure of an (often approved) drug and making small modifications to it. These tweaks can result in enhanced activity of the parent molecule – such as better tolerance, specificity, efficacy – while preserving the original therapeutic activity.

Me-too drug design is a popular strategy in medicinal chemistry, as it leverages on the already available knowledge and research surrounding the initial compound. Firstly, this drastically reduces the time and effort it takes to discover new lead compounds. Secondly, me-too drug design has given rise to many new, improved and sometimes even novel therapeutics!

Lipitor – Improving Upon Existing Statins

Statins are a class of drugs designed to safely reduce the production of low-density lipoprotein, or ‘bad cholesterol’, in our bodies. The first statins to make it onto the market were developed by U.S. pharmaceutical company Merck, beginning in 1987. Having invested heavily in statin research, Merck continued to churn out several generations of statins, each more potent than the last. However, the real jewel in the statin crown was to be uncovered by Pfizer in 1997.

me too statin drugs lovastatin simvastatin pravastatin fluvastatin
Chemical structure of several statin-class drugs. (From left, clockwise) Lovastatin, simvastatin, pravastatin, fluvastatin

Taking Merck’s lovastatin as inspiration, Pfizer developed a me-too statin of its own. Despite being late to the game, ‘atorvastatin’ proved to be a class apart in several human clinical trials. Pfizer marketed atorvastatin as Lipitor, emphasizing its superior potency in an aggressive advertising campaign. But being the 5th drug of its class to be approved, initial projections for Lipitor sales were conservative at best.

atorvastatin chemical structure
Chemical structure of Pfizer’s atorvastatin (Lipitor), designed by borrowing structural motifs from existing statins

Just a year after its launch, however, Lipitor’s sales had skyrocketed past the US$1 billion mark. To this day, it remains the best-selling medicine in history in terms of total revenue generated. Not bad for a me-too drug!

Anafranil – The Innovative Copycat

Some me-too drugs uncover new mechanisms and effects that are not present in previous generations. A case in point is the tricyclic antidepressant clomipramine (Anafranil), developed by Swiss pharmaceutical company Geigy (now Novartis) in 1968. Tricyclic antidepressant drugs had already been discovered ten years earlier, with the pioneers being none other than Geigy themselves.

Pharmaceutical company Geigy’s clomipramine (right) was simply a chlorinated derivative of imipramine (left), their first tricyclic antidepressant.

In that span of time, about 10 more drugs of the same class had already been developed, but Anafranil held a unique advantage. Tricyclic antidepressants work by inhibiting neurotransmitter reuptake in the brain, but their lack of selectivity causes inhibition of sodium and calcium channels, increasing the risk of heart failure in the event of an overdose.

As well as being an effective antidepressant, Anafranil is highly specific to the serotonin receptor while having less of an effect on others1. This led to future antidepressant research efforts surrounding this mechanism of action. Today, selective serotonin reuptake inhibitors (SSRIs) are a widely prescribed class of drugs. The SSRIs fluoxetine (Prozac) and sertraline (Zoloft) see tens of millions of prescriptions each year.

Me-Too Drug Discovery and Innovation

As of 2020, the World Health Organization’s list of essential medicines for a healthcare system consists of over 370 drugs, of which 60% can be considered me-too drugs2. Despite the ubiquity of these drugs, there is considerable controversy surrounding their development, particularly regarding their lack of innovation.

The entire process of drug discovery and development costs roughly US$2 billion per approved drug. By making incremental improvements to tried and tested drugs, pharmaceutical companies often adopt me-too strategies to hedge the risk that often comes with novel innovation.

A Lack of Innovation?

It has long been a concern that me-too drugs are not innovative, as they rely on existing drugs. In fact, the term ‘me-too drug’ was coined in the 1950s as an introduction to the problem of how pharmaceutical companies approached drug design. It was the case that every time a new drug class was discovered, others rushed aboard the bandwagon to develop something similar.

If the profitable strategy in drug discovery is to rely on the groundwork of others, who would willingly step up to develop the first iteration of a new drug class? This lack of innovative development would see fewer novel drugs with new mechanisms of action enter the market. Perhaps more worryingly, research efforts into new treatments for potentially incurable diseases could be diverted to churning out me-too drugs, as companies are likely to see better returns.

The current drug market is saturated with drugs indicated for pain, high cholesterol, heart disease, rheumatoid arthritis, etc. Apart from being commonly diagnosed, many are considered ‘Western’ diseases in that treatment for them is often sought in developed countries. As a result, pharmaceutical companies continue to produce these drugs, knowing there is a market that can afford to pay for them. And what better way to go about drug discovery than with the ‘me-too’ strategy?

Alternative Perspectives

While other disease areas remain underserved, having multiple drugs for a specific indication provides a buffer against drug shortages. This is especially important for drugs that are still under patent, as generic versions of them would not yet be available. Furthermore, having a large array of certain drugs like antibiotics is not necessarily bad, as they may provide alternative treatments against antibiotic-resistant bacteria.

Perhaps a compromise can be reached by regulatory agencies only granting approval to me-too drugs that show considerable improvements over existing ones. Clinical trials usually compare the drug candidate with a placebo to determine efficacy, rarely with existing drugs on the market. Doing this instead would reduce the number of me-too drugs that elicit identical responses, forcing more innovative research aimed at producing tangible improvements.

Room for Both Novel and Me-Too Drugs

Regulatory agencies like the U.S. Food and Drug Administration (FDA) offer fast-track and accelerated review programs for new and novel drugs. These drugs enter the market earlier with longer patent eligibility, generating more revenue for the company that developed them. Incentives for innovation, such as the FDA’s priority review voucher, further reward companies for developing drugs against tropical or rare diseases.

The fact remains that our knowledge of rational drug design remains very primitive. Despite centuries of well-funded research, luck and chance still play a big role in uncovering new and innovative compounds with therapeutic activity. That’s why – from a financial perspective – the me-too drug strategy shows no signs of going away. They provide pharmaceutical companies a means to stabilize their revenues, while also ensuring a healthy supply of alternative options in the case of drug shortages.



Reference

  1. Shorter, E. (2014). The 25th anniversary of the launch of Prozac gives pause for thought: where did we go wrong?. The British Journal of Psychiatry204(5), 331-332.
  2. Aronson, J. K., & Green, A. R. (2020). Me‐too pharmaceutical products: history, definitions, examples, and relevance to drug shortages and essential medicines lists. British Journal of Clinical Pharmacology.

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