Industry Frontiers

In the vast global pharmaceutical market, the field of PD-1 inhibitors has always occupied a crucial and eye-catching position. Among them, Merck's K-drug (pembrolizumab) has long held the throne as the "king of drugs" with excellent efficacy and wide indications. In 2024, it narrowly defeated semaglutide with sales of $29.482 billion, continuing to write a brilliant chapter. However, behind this dazzling light, a storm about the future fate of K drug is quietly brewing. The development and patent disputes of subcutaneous injection formulations, like the sword of Damocles hanging high, profoundly affect the direction of K drug and even the entire innovative drug industry.

Subcutaneous dosage form: a new dawn for patients and pharmaceutical companies

With the continuous advancement of medical technology and the increasing demand from patients, innovation in drug formulations has become an important driving force for the development of the pharmaceutical industry. In this context, subcutaneous injection formulations have emerged, bringing many significant advantages to patients and pharmaceutical companies.

For patients, subcutaneous injection greatly improves the treatment experience and enhances compliance. Traditional intravenous injection often requires patients to spend a lot of time in the hospital, and the administration time of 30-90 minutes not only brings physical inconvenience to patients, but also seriously affects their daily life rhythm. The subcutaneous injection version has completely changed this situation, with the fastest administration taking only 2-3 minutes, greatly reducing the treatment time.

More importantly, subcutaneous injection can be separated from hospital settings, allowing patients to self administer medication at home. This not only improves patients' quality of life, but also reduces the pain and economic burden of traveling to and from the hospital. For example, some cancer patients who have limited mobility or live in remote areas may have been affected by the inconvenience of intravenous injection in the past, but now subcutaneous injection provides them with more convenient treatment options, allowing them to receive treatment more effectively and increasing their hope of recovery.

From the perspective of pharmaceutical companies, subcutaneous injection formulations have enormous commercial potential. On the one hand, developing subcutaneous injection formulations may extend the patent protection period of drugs. Taking Roche as an example, it has successfully extended the patent protection period to at least 2030 by developing a combination of rituximab and hyaluronidase (rituximab Hycela).

Similarly, the launch of Herceptin Hylecta, a subcutaneous injection of trastuzumab, and Phesgo, a combination of trastuzumab and pertuzumab, not only enriched Roche's product line but also brought considerable market revenue. Phesgo has maintained a continuous growth trend since its launch. On the other hand, subcutaneous injection formulations can help pharmaceutical companies expand their market share. With the acceleration of the global aging process and the rise of the incidence rate of cancer, patients have an increasingly urgent need for convenient and efficient treatment.

Subcutaneous injection, with its unique advantages, can attract more patients to choose and stand out in the fierce market competition. In addition, subcutaneous injection can also reduce the production and operating costs of pharmaceutical companies, improve production efficiency, and create more profit margins for pharmaceutical companies.

Layout and promotion of K drug subcutaneous dosage form

Faced with the upcoming patent cliff (K-drug compound patent will expire in 2028), Merck understands the importance of being prepared for the future and has actively laid out subcutaneous injection formulations, viewing it as a key strategic measure to continue K-drug's glory.

In 2020, Merck had a keen eye and chose to collaborate with South Korean company Alteogen to integrate the recombinant hyaluronidase ALT-B4 developed by the latter into the injection formula of K drug. This innovative measure is of milestone significance as it successfully optimized the administration of K drug from traditional intravenous infusion to subcutaneous injection, and achieved a significant breakthrough in extending the injection cycle from once every 3 weeks to once every 6 weeks. This not only further improves patient compliance, but also gives K drug a unique advantage in market competition.

Merck has also achieved remarkable results in clinical research. On November 19th last year, Merck announced the results of subcutaneous injection MK-3475A-D77 for the treatment of critical stage III metastatic non-small cell lung cancer. The data shows that its efficacy is not inferior to intravenous injection, and the administration time is significantly reduced to 2-3 minutes. This breakthrough has laid a solid foundation for the launch of K drug subcutaneous formulations. Based on this, Merck confidently submitted its listing application and stated that it expects the trial to support indications for all solid tumors. If successfully approved, K drug is not only expected to see a significant increase in sales, but also has the potential to obtain an extension of the patent period through its innovative subcutaneous formulation, achieving "longevity" development.

Sniper Attack: Halozyme's Patent Challenge

However, at a critical moment when the subcutaneous formulation of K drug seemed to be advancing rapidly and about to succeed, Cheng Yaojin emerged halfway through. Halozyme, the dominant player in the field of hyaluronidase technology, launched a fierce attack on Merck on the grounds of patent infringement, bringing great uncertainty to the subcutaneous formulation plan of K drug.

Halozyme has a profound technical accumulation and extensive patent layout in the field of hyaluronidase technology, and its invention of hyaluronidase has a history of more than 20 years. In this long development process, Halozyme has established close cooperative relationships with multiple internationally renowned pharmaceutical companies and successfully promoted the approval of multiple biologics containing hyaluronidase for market launch.

These products cover a wide range of therapeutic fields, such as Roche's atezolizumab subcutaneous injection version, Johnson&Johnson's daratumumab subcutaneous injection version, BMS's O-drug subcutaneous injection version, etc. With these successful cooperation cases, Halozyme has achieved rapid revenue growth by collecting royalties, soaring from $100 million in 2021 to $1 billion in 2024, becoming a true "water seller" in the subcutaneous injection field.

Hyaluronidase plays a crucial role in the development of subcutaneous injection formulations. Due to the limited volume of subcutaneous injection, the development of high concentration formulations faces many challenges, and the combination of therapeutic antibodies and hyaluronidase has become the key to solving this problem. Hyaluronidase can significantly increase the maximum injection volume of subcutaneous administration, hydrolyze hyaluronic acid through local injection, reduce intercellular adhesion, and achieve smooth administration

At present, multiple biologics containing hyaluronidase have achieved mass production based on this characteristic, and daratumumab is a typical representative among them. According to a conference call by Johnson&Johnson in mid-2022, the conversion rates from intravenous injection to subcutaneous injection of Daretou in the US and European markets are as high as 85% and 80%, respectively, highlighting the advantages of subcutaneous injection.

The K-drug subcutaneous formulation developed by Merck in collaboration with Alteogen uses the recombinant hyaluronidase ALT-B4 developed by Alteogen. This technological approach is completely different from the practice of most pharmaceutical companies using Halozyme hyaluronidase. However, Halozyme does not endorse Merck's innovative move.

Last October, Halozyme launched a newly engineered modified hyaluronidase Mdase and claimed that its product portfolio has about 100 patents covering enzyme structure, drug delivery applications, and other aspects. The protection period in Europe has been extended to 2032, and in the United States it has been extended to 2034. Halozyme firmly believes that other companies developing and improving hyaluronidase will infringe on its patents and has taken the lead in challenging Merck.

Faced with Halozyme's attack, Merck did not sit idly by. The company quickly submitted an application to the United States Patent and Trademark Office seeking administrative review of seven Mdase patents, attempting to question the reasonableness and scope of their patents. The institution is expected to decide whether to accept this case before June. But Halozyme is confident in its own patents and believes that Merck's questioning will not have a substantial impact on its patents.

Game outcome: Three possible directions

At present, the patent dispute between Halozyme and Merck is in a tense standoff phase, and the outcome of this game will have a profound impact on the future of K drug. There are roughly three possible outcomes:

The first outcome is that Merck chooses to compromise and accept the "milestone+royalty" cooperation model proposed by Halozyme, and the two parties further negotiate to determine a reasonable sales sharing ratio. For Merck, although this choice means sacrificing a portion of profits, it can avoid market access risks caused by patent disputes, ensure the smooth launch of K drug subcutaneous formulations, and continue to play an important role in the market.

Based on K's sales of up to 29.5 billion US dollars in 2024, even if the subcutaneous version only accounts for 30% of the market share, Halozyme will still receive a considerable share; If it can achieve an 80% subcutaneous share similar to that of daratumumab, its returns will be even more substantial. Therefore, for Halozyme, this is a determined sniper battle.

The second outcome is that Merck chooses to be tough to the end. If the US Patent and Trademark Office accepts Merck's application, both parties will inevitably be embroiled in a lengthy litigation tug of war. Looking back at the history of Merck and BMS in the PD-1 patent dispute, such lawsuits often take many years, are complex and full of uncertainty.

This is highly likely to seriously affect the marketing progress of K drug subcutaneous preparations, causing them to miss the best market promotion opportunity. In the fiercely competitive pharmaceutical market, time is life. Once delayed, K drug may not only face the risk of market share being eroded by competitors, but also have a negative impact on Merck's overall performance and market reputation.

The third outcome is that Merck successfully proves the independence of its technology. Alteogen's ALT-B4 uses a differentiated sequence and has not been disclosed in the Halozyme patent. If Merck can provide sufficient evidence in this patent dispute to prove the uniqueness and non infringement of its technology, it may be able to break the blockade of Halozyme. However, even so, this process will inevitably consume a lot of time, manpower, and financial resources, which may also affect the marketing rhythm of K drug subcutaneous preparations.

Industry warning: multidimensional thinking on the development of innovative drugs

The patent dilemma faced by K Pharmaceutical this time is like a mirror, reflecting clearly the many challenges and risks faced by the innovative pharmaceutical industry in its development process, and also sounding the alarm for the entire industry, bringing profound enlightenment.

In the process of developing innovative drugs, expanding indications is undoubtedly the foundation. Only by continuously exploring the therapeutic potential of drugs in different disease fields and expanding their applicability can we provide solid market support for the long-term development of drugs. For example, K drug has achieved significant results in the treatment of various cancers such as lung cancer, melanoma, and colorectal cancer by continuously expanding its indications, thus becoming a widely used anti-cancer drug worldwide.

Formulation optimization is an important means of building a moat for innovative drugs. With the advancement of medical technology and the diversification of patient needs, novel, convenient, and efficient dosage forms can significantly enhance the competitiveness of drugs. The emergence of subcutaneous injection formulations is in line with this development trend, bringing better treatment experiences to patients and gaining market opportunities for pharmaceutical companies. However, innovation in dosage forms is not always smooth sailing, and patent issues often follow closely, becoming a key factor restricting the development of innovative drugs.

Patent layout requires comprehensive planning and proactive measures. In the early stages of innovative drug development, pharmaceutical companies should fully consider the issue of patent protection and develop scientific and reasonable patent strategies. Not only should we provide comprehensive patent coverage for core technologies, but we should also closely monitor patent developments within the industry to avoid the dilemma of patent infringement during the research and development process. Meanwhile, pharmaceutical companies can also achieve resource sharing and complementary advantages through reasonable patent cross licensing, collaborative research and development, and jointly promote the development of the innovative pharmaceutical industry.

In addition, as cancer treatment gradually moves towards chronic disease management, subcutaneous preparations, as a more convenient and efficient way of administration, are becoming a battleground for major pharmaceutical companies. The competition in this field is also rapidly spreading globally, with Roche BMS、 Junshi Biotechnology, Hengrui Pharmaceutical, BeiGene and many other enterprises are laying out their presence, and the competition in the future will be extremely fierce. In this fierce competition, enterprises should not only focus on technological innovation, but also pay attention to intellectual property protection, market promotion, and maintaining relationships with partners. Only by comprehensively improving their own strength can they stand invincible in market competition.

The subcutaneous dosage form dispute encountered by K drug is not only a challenge for Merck, but also a microcosm of the development process of the entire innovative pharmaceutical industry. It reminds us that in the pursuit of innovation and breakthroughs, pharmaceutical companies need to remain vigilant at all times, fully recognize the mutual influence and constraints of various factors such as patents, technology, and markets, and adopt more stable and scientific development strategies to meet future challenges and opportunities, bringing more effective therapeutic drugs and better health and well-being to patients worldwide.

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Source: Xianji.com

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