PD-1 has received little attention recently, and the development of related drugs has not been smooth on a global scale.
Roche’s TIGIT-targeted drug combined with PD-1 trial failed twice in the past two months, and both were phase III trials. Roche is a recognized pioneer in TIGIT targets, and now the two failures have made the future of TIGIT confusing, and it has begun to re-examine the myth of PD-1 combination therapy.
However, there are new attempts that have succeeded.
In March of this year, the US FDA approved a new drug called Opdualag from Bristol-Myers Squibb for the treatment of patients with unresectable or metastatic melanoma. This new drug consists of a fixed-dose combination of PD-1 product O and LAG-3 antibody drug relatlimab. Compared with O-drug alone, the median progression-free survival of melanoma patients who received the combination therapy more than doubled.
One step ahead of TIGIT, LAG-3 becomes the third immune checkpoint that has been proven effective and approved for marketing after CTLA-4 and PD-1.
LAG-3 has been introduced as early as the 1990s. Due to the complex mechanism of action, the first patented drug was not available until 30 years later. The combination with PD-1 gave LAG-3 an “way out”.
Since 2017, the number of new clinical trials in combination with PD-1 in the world has remained above 500. At its peak in 2019, it approached 800. CTLA-4, VEGF/VEGFR, EGFR, TIGIT… Each one was “highly hoped” when it first appeared. Can the success of LAG-3 maximize the value of PD-1?
Global PD-1 monotherapy/combination therapy new clinical and patient enrollment (2014-2020)
Next immune checkpoint
LAG-3 is hardly a new face.
LAG-3 was first discovered in 1990 by French immunologist Frédéric Triebel. In order to better engage in related research, he established a company called Immutep in 2001, which specializes in “deadly fighting” this target. In Triebel’s own words, it is a “pure LAG-3 company”.
At present, major pharmaceutical companies such as GSK, Novartis, Pfizer, Merck & Co., have chosen to cooperate with Immutep to develop LAG-3. Immutep’s own LAG-3, which has progressed the most, has also entered Phase II clinical trials.
LAG-3 has been in development for over 30 years primarily because of its complex mechanism of action.
LAG-3, the full name of lymphocyte activation gene 3, is a transmembrane protein mainly expressed on the surface of immune cells such as activated T cells and NK cells. The principle of LAG-3 is similar to that of PD-1. If the LAG-3 pathway can be inhibited, the body’s own immune system function can be restored and tumor cells can be killed.
However, the mechanism by which LAG-3 interacts with its ligands is unclear. In 1992, Triebel’s team confirmed that a molecule called MHC II can interact with LAG-3, which became one of the main research and development ideas followed in later generations. Merck’s LAG-3 drug MK-4280, which has been in Phase III clinical trials, is based on this principle.
But in addition to MHC II, LAG-3 can also bind to many ligands such as FGL-1, Gal-3, α-syn, etc. How many, no one can say Unclear, this makes it much more difficult to develop drugs. Immutep could not find investors for a while because it only made this one target.
With the launch of CTLA-4 drug ipilimumab, O drug, and K drug, immunotherapy has gradually received attention. Various research forces have gradually focused on immune drugs, and LAG-3 has only been rediscovered in recent years.
According to the biomedical media Endpoints, Bristol-Myers Squibb once regarded LAG-3 as “the forefront of immunotherapy.”
However, early clinical results from various companies have shown that LAG-3 monotherapy has limited efficacy. A Phase I clinical study of Merck MK-4280 showed that the disease control rate and objective response rate of the drug were only 17% and 6%, respectively.
LAG-3’s future is clouded by a cloud.
Combination therapy a breakthrough
Single drug does not work, so Bristol-Myers Squibb began to try combination drugs.
In September 2017, Bristol-Myers Squibb said that the LAG-3 antibody relatlimab has achieved good results in combination therapy with O drug. A trial targeting melanoma indications showed that the objective response rate of patients expressing LAG-3 in immune cells around the tumor reached 18%, compared to only 5% with O alone. Bristol-Myers Squibb believes the results confirm the effectiveness of LAG-3.
2017 is a critical year because it was the last year that O drugs outsold K drugs. Since then, Drug K has been leading the way, and Drug O has almost disappeared in the world.
O medicine urgently needs to find a chance to make a comeback. At the American Society of Clinical Oncology in 2021, Bristol-Myers Squibb took out the phase II/III clinical trial of LAG-3, showing that the combined use of O-drug for melanoma has significantly improved the patient’s survival cycle.
Image source: Huachuang Research
In September of the same year, the combination therapy of relatlimab and O drug was granted priority review status by the FDA. In March this year, the LAG-3 inhibitor Opdualag was launched, becoming the world’s first LAG-3 drug launched more than 30 years after its target was discovered.
In addition to Bristol-Myers Squibb, most of the LAG-3 products under development around the world also choose the idea of combination therapy. According to the statistics of WuXi AppTec, as of April this year, more than 20 LAG-3 therapies have entered the clinical stage around the world, of which 14 have entered the second and third stages of the highest clinical stage.
Roche, F-star Therapeutics, Zai Lab, Innovent, etc. have all chosen to develop bispecific antibodies jointly with PD-1. Those who choose to do monoclonal antibodies also mostly consider the combination situation. For example, Merck’s MK-4280, which has entered phase III clinical trials, is partnered with K drug.
At the end of 2021, BeiGene bought a LAG-3 antibody from Nanjing pharmaceutical company Weilizhibo at a price of nearly US$800 million. Wang Lai, the company’s global R&D leader, said that the introduction of This product is considered to have “expected combination potential” in combination with PD-1 and other tumor immune drugs.
At present, domestic pharmaceutical companies such as Hengrui, Baiji, Innovent, and Zai Lab have already deployed LAG-3, but the research and development progress is not fast.
Can it be widely used
LAG-3’s potential has been proven, but there is still a lot of controversy surrounding it.
Endpoints reports that one of the major debates about LAG-3 in the scientific community today is whether the target “can be transformative for other cancers.” Success in melanoma, can it be replicated in other indications? This school of thought argues that the effects of LAG-3 antibodies are “highly tumor-specific” and that not all cancers can be treated with it.
Merck, of course, will not watch Bristol-Myers Squibb come back, ready to fight back the controversy with facts. Recently, Merck announced that it will announce the results of a phase I/II clinical trial of the combination of LAG-3 inhibitor MK-4280 and K drug for the treatment of relapsed/refractory classical Hodgkin lymphoma. It is said to be very effective.
In addition, Immutep, the company that first developed LAG-3, will also publish clinical data of its LAG-3 product in combination with K drug in the treatment of non-small cell lung cancer. Existing data show that the combination therapy can also achieve an objective response rate of about 31% in patients with no or low PD-L1 expression.
Existing data appear to confirm that the effects of LAG-3 can be replicated in other tumors. However, until the final product is launched, no one can say that the result is not good.
Bristol-Myers Squibb is all set. Opdualag is priced at about $27,000 a needle, and the company is optimistic that sales of this product will exceed $4 billion by 2029. At that time, if the O medicine works hard, the two together will not necessarily be much lower than the K medicine.
Foreign giants have entered the stage of segmenting the market, and Chinese companies are finally starting to do so. On May 18 this year, Sino Biopharmaceutical announced that its subsidiary, Chia Tai Tianqing, bought the global rights to a LAG-3 product from Servier.
Prices haven’t been announced, but Global Equity certainly isn’t cheap.
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