5 Strategies to Make New Drugs Surpass Their Predecessors

First-in-class (FIC) drugs are relatively rare, and even after a mechanism is validated by an FIC drug, it may still give rise to multiple large products. Competing to become best-in-class (BIC) or a fast me-too drug might be the most important competitive space for new drug innovation, with strategies being relatively mature. The FIC drugs that complete proof-of-concept (POC) are usually the result of repeated optimization. What we call BIC or me-better refers to improving upon what others have already optimized to offset latecomer disadvantages in market competition.

It’s often said that learning is never-ending, and any drug has room for further optimization. However, modern FIC drugs rarely have obvious flaws. The days of needing three daily doses or drugs unable to saturate targets at maximum tolerated doses, as was common in the 1980s, are largely behind us. Therefore, simply extending half-life or improving affinity rarely results in BIC drugs today. Although there are exceptions where mechanisms with smaller windows might randomly produce a better balance of efficacy and safety without explicit design strategies, generally speaking, becoming a true me-better drug requires taking some technical risks. In this era, surpassing predecessors requires determination and courage, and today we’ll discuss those strategies.

First-in-Indication

The strategy most likely to achieve overtaking is finding larger or more unpredictable markets through new indications, but this also carries higher risk—otherwise, the FIC drug wouldn’t have overlooked these indications. New indications may come from serendipitous discoveries. For example, SGLT2 inhibitors, developed as diabetes drugs, were later found to treat heart failure. This "serendipity" was in part due to Eli Lilly taking a risk with cardiovascular outcome trials for Jardiance.

A similar example is the now wildly popular GLP drugs for weight loss, initially marketed 20 years ago as diabetes medications. While they became blockbuster drugs in that space, their real explosion in popularity came as weight-loss treatments. The weight-loss effect wasn’t clear in preclinical studies but was discovered later in clinical trials.

Sometimes, a drug may find new uses after long-term widespread use, though the FIC drug’s patent might have expired by then. Developing a new molecule to replicate already observed clinical effects is a low-risk but potentially lucrative strategy. From ACE inhibitors like Altace in the 1980s to Entresto in this century, moving from treating hypertension to heart failure, or CD20 antibodies like Ocrevus moving from CLL to MS, such shifts have happened. Some new indications also arise from intuition, such as lenalidomide (technically a derivative of thalidomide), originally the antagonist of a tragedy but later hailed as a king of small molecule drugs due to its anti-angiogenesis properties. Recently, German doctors successfully used CD19 CAR-T therapy for untreatable SLE patients, another such example.

For mechanisms with broad activity, development directions can be numerous. In these cases, choosing the right development strategy might be more critical than discovering the drug molecule first or even achieving proof of concept. The competition among PD-1 drugs is the most representative example of this. While Bristol-Myers Squibb took the biggest risk and achieved clinical validation with Opdivo first, it missed critical opportunities, like in first-line NSCLC treatment, allowing Keytruda to surpass it to become a top seller. AstraZeneca, coming from even further behind, distinguished itself with Imfinzi, thanks to outstanding phase 3 data in NSCLC treatment, securing a substantial market share.

Although these are me-too drugs in terms of mechanism, their profitability comes from targeting new indications, which is much riskier and more challenging than simple follow-ups.

Improving Selectivity

Selectivity isn’t typically an issue for antibody drugs, but it can be a weakness for small molecules. For example, DPP4 inhibitors are important second-line diabetes drugs. Novartis' Galvus was the first to complete proof-of-concept for this mechanism, but its reversible covalent warhead (cyanide) made it slightly less selective.

Nevertheless, Merck quickly brought Januvia to market with better selectivity, making it the unquestionable best-in-class drug. The third-generation EGFR inhibitors improved selectivity for wild-type EGFR, reducing toxicity and solving the T790M resistance issue. Early CDK4/6 inhibitors lacked sufficient selectivity to resolve toxicity issues, but Pfizer’s Ibrance succeeded with better selectivity. As mentioned earlier, KarXT tackled selectivity problems through a combination strategy.

Improving Pharmacokinetics/Drug Distribution

Improving pharmacokinetic properties has always been a crucial strategy for creating me-better drugs. Since insulin's launch in 1923, there have been various products designed with different release kinetics for different clinical scenarios. Even after 100 years, several insulin products remain blockbuster drugs, giving Novo Nordisk the resources to develop GLP-1 drugs. The GLP-1 class of drugs itself represents a gradual improvement in pharmacokinetics, mainly by extending half-life to reduce injection frequency, evolving from three times daily to once a week, with some research now exploring once-a-year dosing. Abraxane is an example of improving drug distribution to become a leading product.

Prodrug designs that alter the release and distribution of active drugs, especially in the context of ADCs and conjugated radiopharmaceuticals, have been particularly successful pharmacokinetic-based drug designs. Irinotecan, once a struggling me-worse TOP1 inhibitor, became a hot chemotherapy drug after altering its release and distribution through antibody conjugation. Though GLP-1 drugs are effective for weight loss, their side effect of muscle loss is increasingly questioned. A weight loss and muscle-building drug, HU6, which is the prodrug of the notorious DNP, is already in phase 3 clinical trials.

Increasing Activity

Activity is the most fundamental property of a drug, so optimizing it is the most critical task in drug development. However, with today’s technology, FIC drugs leave little room for activity optimization, making it a rare foundation for BIC design. Historically, one successful example of increasing activity to overtake competitors is Lipitor. Though it was the fifth drug of its kind to be marketed, its slightly superior lipid-lowering capability became an advantage that Pfizer’s powerful marketing team leveraged to the fullest.

The "know your numbers" campaign became one of the most successful marketing campaigns ever. Additionally, Pfizer conducted large COVT trials in certain populations, which further boosted Lipitor’s growth. Some targets, like Kras, were once deemed undruggable due to limitations in ligand activity, but optimizing activity became the key to success for drugs targeting these areas.

First-in-Modality

After complex, non-oral nucleic acid or antibody drugs validate a target, developing oral small molecules as next-generation products can be a successful strategy. Important targets like PCSK9, GLP, PDL1, IL17, and TNF have all been the focus of small molecule projects, but technical limitations have resulted in lower success rates. Pfizer's ATTR drug Tafamidis and Roche's SMA drug Risdiplam are two relatively successful examples.

Similarly, small molecules can use irreversible covalent inhibitors to increase the activity of reversible inhibitors, as seen with second-generation EGFR inhibitors. PROTACs, which degrade proteins rather than inhibit them, offer another strategy for drugs like AR and ER.

Dual-Function Molecules

Many diseases are caused by abnormalities in multiple proteins or different proteins depending on the disease at the molecular level. Dual-function molecules, from small molecules to antibodies, are a potential area of exploration. Multi-target small molecule drugs mainly target related proteins, such as multi-kinase inhibitors, where multiple targets are controlled simultaneously. In some cases, it is nearly impossible to achieve selectivity, so they are conveniently called multi-target drugs.

There are very few small molecules that truly target multiple unrelated targets; bendamustine is one example. While some bispecific antibodies have been approved, most use molecular linkers, and few truly target two pathogenic proteins. The highly popular GLP/GIP dual-target drug is an exception, but its mechanism is complex, and it remains debated whether both targets are responsible for its effects.