Analysis of New Drug R&D Strategies: Advantages of First-to-Market Drugs Shrinking while Latecomer me-better Drugs Surpassing

In the new drug development, pursuing the marketing of the first product of its variety is always the highest goal of pharmaceutical enterprises, as the first drug marketed can enjoy a period of market exclusivity, thus to rapidly occupy the market, and furthermore, the first marketed in the new technology and new field will be long under the spotlight and be favored by more capital, however, being first does not necessarily mean the market recognition, the pioneering new products always face many unknown challenges and would easily turn from a "pioneer" to a "martyr", and the latecomers have more opportunities to achieve higher success by stepping on the "bodies" of "martyrs". The strategy to pursue the First-to-Market or me-better product becomes more important in the drug development process.

1.    "Pioneer" turning into "martyr", latecomers surpassing

When applying new technology in the market, the first products that reach the finish will be much favored but also confronted with many unknown traps. ADCs and bispecific antibodies have experienced highs, lows, and regaining popularity in the antibody therapy field, and such experience is also the process of: successful marketing of the first products that represent the new technology, poor market performance thereof after marketing, and latecomers regaining recognition.

1.1  ADC field

Pfizer’s ADC Mylotarg that targets CD33 was approved by FDA in 2000 for treating AML (acute myeloid leukemia), to become the first marketed product in the history of ADCs, however, Mylotarg did not achieve the expected success as a pioneer, with the average annual sales of USD 33 million during 2006-2010, barely growing. In addition to the unsatisfactory market performance was the gradually exposed safety problem in the clinical trial. The drug was eventually removed from the market in June 2010, to sadly turn from a pioneer to a "martyr".

In 2011, one year after Mylotarg was removed from the market, Adcetris (targeting CD30) of Takeda and Seattle Genetics was successfully marketed, and in 2013, Roche’s new-generation HER2-targeting ADC Kadcyla developed based on own Herceptin was successfully marketed. Sales of the two grew year by year after marketing (Fig. 1), marking ADCs’ gradual maturing. Pfizer reset the technical scheme after analyzing the early-stage clinical data to bring Mylotarg to the market again in 2017.

1.2  Bispecific antibody field

In the bispecific antibody field, Removab was approved for marketing in 2009, to become the first to test the water. Unfortunately, its market performance was unsatisfactory after its marketing, with sales in 2010-2012 separately of USD 3.32 million, 4.43 million, and 4.54 million. Thereafter, it was hard to find the drug on the market. The drug was quietly removed from the market in 2017. Removab is a hybrid of two maternal antibodies from mice and rats and achieves double-targeting, however, fully mouse antibodies have no longer been the mainstream in the antibody field.

Blincyto is a key product based on BiTE technology that was obtained by Amgen after acquiring Micromet Company for USD 1.2 billion in 2012, and was approved by FDA in 2014 as a second-line therapy for Ph chromosome-negative pre-B cell acute lymphoblastic leukemia (ALL). Despite the much controversial expensive expenses of USD 178,000 for two cycles of therapy, its performance was not disappointing after the marketing, with total sales in 2015 and 2016 separately reaching USD 77 million and 115 million, which achieved the forecast of the analyst at the beginning of marketing: the goal of annual sales reaching at least USD 100 million. The performance of Blincyto seemed to be average, however, it was much better than that of Removab that became a "martyr". More importantly, Ph chromosome-negative pre-B cell ALL is an extremely rare disease that attacks about 6,000 people in the U.S. every year. Currently, what people expect the most is the third member of the bispecific antibody family—emicizumab that was approved to treat hemophilia A in 2017.

2.    To be First-to-Market or me-better?

2.1  Competition in the ophthalmology

As to the competition in the ophthalmology, Avastin (Anti-VEGF-A) was first approved for wAMD (wet age-related macular degeneration) in 2005; one year later, Lucentis (Anti-VEGF-A monoclonal antibody fragment (Fab)) from the same maternal antibody with Avastin was the first to be approved for marketing. During the 5 years thereafter, Lucentis had no challenger and its sales continued to increase, to become the absolute blockbuster product in the ophthalmology (Fig. 2). In 2011, with the marketing of Regeneron’s VEGF inhibitor Eylea (aflibercept), the good times of Lucentis were gone. As a VEGFR 1 -D2/VEGFR2 D-Fc-fusion protein, Eylea can neutralize VEGF-A, VEGF-B and PlGF. Not only can it neutralize more targets, it is more convenient to use: patients need to be consecutively injected once every month in the first 5 months, and then examined and injected once every two months (8 weeks), while patients need to be administered Lucentis every month. The reduction of intravitreal injections will make patients have better compliance. Eylea thoroughly defeated Lucentis no matter in terms of clinical use effect or patient compliance, which was more intuitively shown in market sales (Fig. 2).

2.2  The phenomenal TNF-α target

TNF-α has become a legend in the history of targeted drugs. In 2017 just past, Humira (adalimumab), Enbrel (etanercept) and Remicade (infliximab) that target TNF-α separately ranked first, fourth, and seventh (Fig. 3) in the list of top 10 drugs by global sales. As a chimeric human-mouse antibody, infliximab was first marketed in August 1998, two months later, etanercept, a Fc-fusion protein, was marketed, and four years later, adalimumab, the first fully human antibody obtained by phage library screening, was marketed. There was only a 2.5-month interval between the marketing time of infliximab and etanercept, and the subsequent market performance of the two has been on a par. The two have succeeded with the strategy of competing for First-to-Market product. Compared to infliximab, adalimumab that was marketed four years later is a true "me-better", and its subsequent market performance has been dominating and ranking first for years in terms of global sales.

Lucentis, etanercept and infliximab were successful in terms of the strategy to compete for First-to-Market drug. It would be hard to imagine how much market they could occupy or whether they could survive on the market in the face of impacts from Eylea or adalimumab, if they did not have the accumulation in the first few years. On the other hand, the me-better strategies of Eylea and adalimumab were more successful. Getting rid of the unfavorable situation after the marketing and realizing latecomer surpassing is itself a marvelous achievement.

3.    Summary

As the competition in the pharmaceutical industry becomes increasingly intense, the interval of marketing time of the first marketed drug, second and third marketed drugs has been greatly shortened. The interval between the approval of the first and second drugs of the same variety by the U.S. FDA was averagely 4.9 years during 1998-2004; this interval was reduced to 2.5 years during 2005-2011; it has been further shortened in recent 6 years, for example, in the tumor immunotherapy field, after Keytruda was approved in September 2014, its biggest competitor Opdivo was approved for marketing just 6 months later; in the psoriasis field, the anti-IL-17 monoclonal antibody: Cosentyx was approved in January 2015, while 14 months later, Taltz was successfully approved; in 2015, the interval between the approval of the anti-PCSK monoclonal antibody Praluent and Repatha was only a month; in 2017, the most eye-catching drugs were CAR T-cell therapy Kymriah and Yescarta, and the interval of their marketing time was only 2 months.

The shortening of the product marketing interval has gradually reduced the advantages brought by the exclusivity enjoyed by First-to-Market products. In the situation of products competing for marketing, doing me-better products will apparently lead to bigger advantages, however, as the studies are started almost at the same time, there is hardly time to improve own products by studying defects of competitors; as a result, pursuing fast marketing will become the inevitable choice; the First-to-Market products, no matter whether they are the best or not, can always gain returns from the market. However, in terms of use of new technology in new field, pioneering products often come with high risks, and First-to-Market products are often crushed by more competitive latecomers. In the face of the fierce competition for First-to-Market products, when it is unlikely to catch up with the First-to-Market manufacturers in the short term, perhaps settling down, drawing lessons from pioneering products and stably doing me-better products will be a better choice.