The 'medicine king' laurels will eventually change hands, but innovation will not die

In 1986, the annual sales of Thai Gasmei exceeded $1 billion, and the pharmaceutical industry gave birth to a new word that countless companies yearned for, "blockbuster drugs". 16 years later, the statin Lipitor from Pfizer broke the "bombshell" ceiling with annual sales of more than $5 billion and topped the sales list that year.

In 2012, Lipitor, the "medicine king" who won the 10th consecutive term, completed the handover with the new "bombshell" Humira, which has an annual sales record of 9.265 billion US dollars. At this point, a new chapter has opened in the history of world pharmaceutical sales.

Back in 2000, White, then CEO of Abbott, waved his hand and spent $6.9 billion to acquire Knoll, a subsidiary of the famous chemical company BASF in Germany, to obtain a drug under development called D2E7. Three years later, D2E7 reappeared under the name "Humira", "overcoming difficulties" all the way, and finally reached the throne of "Medicine King" in 2012.

In 2013, Abbott split the company into two parts, one still operating the traditional business of Abbott, and the other part of the new company focused on biopharmaceutical innovation - AbbVie. The "medicine king" laurel was therefore placed in AbbVie's home, and this release was another ten years (excluding the new crown drug).

01

"Heroic twilight"?

Humira received FDA approval in December 2002 as the world's first fully human anti-tumor necrosis factor monoclonal antibody (TNF-α active monoclonal antibody). In September 2003, Humira was approved by EMA and approved for import in China in February 2010.

TNF-α inhibitors are mainly used in the treatment of rheumatic immune diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA) and juvenile idiopathic arthritis (JIA). In 1998, the world's first TNF-α inhibitor, Infliximab (from Johnson & Johnson), was approved for marketing, opening the era of biologics led by TNF-α inhibitors for the treatment of rheumatoid diseases such as rheumatoid arthritis.

Although Humira is the third TNF-α inhibitor approved by the FDA, it performs the best. First approved in the first half of this year, Humira's cumulative sales revenue exceeded $200 billion, and last year's sales revenue exceeded $20 billion. Arguably, Humira is the most important source of income since AbbVie's inception.

However, in the first quarter of 2019, Humira's sales fell for the first time in recent years, down 5.6% year-on-year, and its sharp decline in sales in the European market may be due to its large proportion. As early as 2018, Humira's patent in Europe expired, and Humira's sales in Europe began to decline due to the impact of generic drugs. In fact, not only Humira, but the entire TNF-α inhibitor market has been declining since 2018.

In addition to the European market, Humira's patent in China expired in 2017. However, Humira has been mediocre in the Chinese market, with less than 1% of Chinese patients using Humira due to its high selling price. Last year, all 8 major indications listed by Humira in China entered the national medical insurance catalog, and the price was reduced from 7600 yuan to 1290 yuan per stick.

And in the United States, Humira's "home", its patents will also expire in 2023. Amgen will launch a generic version of Humira in late January and plans to focus on education, patient experience and real-world evidence. The Humira generic drug Abrilada from Pfizer has also been approved by the FDA for the treatment of certain inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, etc., and will be launched in 2023. In addition, generic drugs from MNC such as Novartis, Boehringer Ingelheim and others are also watching.

02

Fight for Humira

To defend Humira's market exclusivity, AbbVie built walls in every dimension.

At present, Humira has more than 10 approved indications worldwide, covering respiratory, ophthalmic, nervous system, infection, musculoskeletal system, immune regulation, gastrointestinal system, dermatology, cardiovascular system, inflammation, etc., among which the indication of rheumatoid arthritis has been around the world for more than 10 years. AbbVie is still working on Humira monotherapy and combination therapy at this stage.

In addition to expanding indications, AbbVie has built a solid patent jungle for Humira. To date, AbbVie has filed about 250 patent applications for Humira, of which 130 patents have been granted, and the enhanced patent protection has indeed extended Humira's legal monopoly in the United States for 6 years. Even so, there are still many generic drugs trying to "break" the fortress, and AbbVie has also been rushing to various lawsuits against Humira generic drugs in recent years.

Fortunately, AbbVie has "settled" with a number of generic drug companies: it has signed licensing settlement agreements with 9 companies, including Amgen, Samsung Bioepis/Merck, Novartis, Mylan, and Pfizer. According to the terms, these pharmaceutical companies can produce and sell generic drugs, but must give AbbVie a certain royalty; For generic drugs that have already passed FDA approval, their launch in the United States must be delayed until 2023.

It is worth mentioning that AbbVie has also launched a patient support program called "Humira Complete", which includes help such as nurses, insurance and injection training, providing patients with more than the drug itself. However, it's not clear how much help exactly a Humira Complete will be.

Even if AbbVie did everything in his power to defend Humira, it would not be able to withstand the time. As the patent deadline drew closer, AbbVie began to face up to the challenges Humira would eventually face and gradually shifted his focus.

Over the past few years, AbbVie has tried to reduce his dependence on Humira. In 2019, Humira's revenue still accounted for more than half of its revenue, but that share has dropped to 36% in the first half of this year.

03

"Successors"

On October 21, AbbVie announced that the FDA has approved its oral JAK inhibitor, Rinvoq, for the treatment of adults with active non-radial axial spondyloarthritis (nr-axSpA) with objective signs of inflammation who respond or are intolerant to tumor necrosis factor (TNF) blocker therapy. This is the sixth FDA approval for Rinvoq, making it the first and only drug to be approved under both conditions.

Rinvoq's four new indications have also been approved by the FDA within five months, which can be described as a shining "new star" for AbbVie.

Another thing AbbVie has high hopes for is the new anti-inflammatory drug IL-23 inhibitor Skyrizi, which has been approved for plaque psoriasis, psoriatic arthritis, generalized pustular psoriasis, erythrodermic psoriasis and other indications, which is the drug with the largest number of approved indications among all IL-monoclonal antibody products. Skyrizi also beat Novartis' Cosentyx in 2020 with a head-to-head phase III efficacy in adults with moderate to severe plaque psoriasis.

These two "successors" have lived up to AbbVie's trust, and revenue has climbed rapidly since commercialization. In the first half of 2022, Rinvoq's revenue reached $1.057 billion, a year-on-year increase of 55.1%; Third-quarter sales were $695 million, up 59.3% year-over-year. Skyrizi is growing at an even faster rate, with revenue of $2.192 billion in the first half of this year, a year-on-year increase of 75.7%; Third-quarter sales reached $1.397 billion, a year-over-year increase of 75.4%.

Skyrizi and Rinvoq are accelerating coverage and transcendence of Humira in terms of indication expansion. AbbVie expects the combination of Skyrizi and Rinvoq to generate a total of $15 billion in revenue in 2025, which may be able to compensate for the loss of sales caused by Humira's biosimilar impact.

In the field of immunity, AbbVie also has ABBV-154, ABBV-159, ABBV-599, ABBV-668 and other projects in the development of immune-mediated diseases, ulcerative colitis, systemic lupus erythematosus, polymyalgia rheumatica, rheumatoid arthritis and other clinical trials.

In terms of expanding the pipeline, AbbVie is also constantly moving. On October 20, AbbVie announced the acquisition of DJS Antibodies, acquiring its potential first-in-class lysophosphatidic acid (LPA) LPAR1 antagonist, which is currently being developed for the treatment of idiopathic pulmonary fibrosis and other fibrotic diseases.

In June, AbbVie announced the acquisition of TeneoBio's subsidiary TeneoOne and its main product candidate, TNB-383B (BCMA/CD3 dual antibody). In addition to continuing to expand its strong areas of hematological cancers, AbbVie also has a presence in ophthalmic gene therapy and aesthetic medicine: In May 2020, AbbVie announced the completion of the acquisition of Allergan, acquiring its blockbuster aesthetic product, Botox, for a $63 billion transaction.

04

The situation is undecided

In a report by Evaluate Pharma, Humira is no longer on the list of the top 10 best-selling drugs in the world in 2028, but Skyrizi and Imbruvica, also from AbbVie, are among them.

Clearly, AbbVie's preparations for the "Medicine King" handover are playing a role. As an oral BTK inhibitor, Imbruvica was developed and commercialized by Johnson & Johnson in collaboration with AbbVie. In China, Imbruvica has also been approved for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and Fahrenhei macroglobulinemia (WM).

But there is a frustrating side to these efforts, and Rinvoq has not been so lucky to make the list, perhaps because of the FDA's boxed warning for all JAK arthritis drugs. Although the safety of JAK inhibitors has been a concern, their market in 2021 was still nearly $9 billion. According to Frost & Sullivan, the market size is expected to grow to $30.5 billion by 2030, with a compound annual growth rate of 8.0%. The potential of JAK inhibitors remains enormous.

In addition to JAK, the market size of new target drugs such as IL12/23, IL17, and IL4/13 has also accelerated in recent years. At present, TNF-α inhibitors are still in the forefront of sales in the global autoimmune drug market, but the market has passed its peak and may continue to shrink in the future.

Taking a step back, the drugs on the list may seem brilliant, but many of them will face the pressure of the patent cliff. In the next decade, BMS/Pfizer's Eliquis, AbbVie/Johnson & Johnson's Ibrutinib, Johnson & Johnson's Stelara, Gilead's Biktatvy and other blockbuster drugs will face the problem of what to do after the patent protection period. The impact of the Inflation Reduction Act (IRA), passed in mid-August, on Medicare drug price negotiations is also unknown.

It is important to develop new indications and maintain the original drug status, but finding possible diversified development is also an important part of strategic development. It is not difficult to see that in recent years, multinational large pharmaceutical companies have frequently adjusted their organizational structure, or expanded their pipelines through mergers and acquisitions and cooperation to seek further development.

In September last year, Merck spent 11.5 billion yuan to reach a merger agreement with Acceleron, and acquired the drug Sotatercept. In October this year, the phase III TELLAR clinical study of the drug for pulmonary hypertension (PAH) reached its primary endpoint. In late August, Novartis announced that it would focus on innovative drugs and plan to spin off its pharmaceutical unit, Sandoz. In September, Novartis invested $300 million in next-generation biotherapies, including API and drug product development.

In addition to the innovation of the drug itself, the study of "organoids" has gradually become "fragrant". As a simulation of real organs and physiological systems of the human body, organoids are of extraordinary value in clinical precision medicine (the development of personalized treatment plans for patients) and preclinical drug development. Pfizer, AbbVie, Johnson & Johnson and other MNCs are all competing in this field.

In August this year, the FDA approved a new drug (NCT04658472) based entirely on "organoid chip" research to enter clinical trials, which is the first time in the world that a drug that has not been tested on animals has been approved into clinical trials. This means that the "organoid on a chip" experiment replaces traditional animal experiments for the first time and is officially recognized. If it goes well, it may get rid of some of the limitations of clinical trials and bring breakthroughs to drug development.

No target is absolutely "safe", and meeting unmet clinical needs is the meaning. No medicine can always be the "medicine king", but there will always be medicine to become the "medicine king".

Veterans don't die, and the torch is passed on.