Vertex (Futai Pharmaceuticals) has a long-standing reputation. It has worked in the field of rare diseases for more than ten years and has created an orphan drug blockbuster trikafta with annual sales of over $10 billion. Today, the company has opened up new horizons in another field. Recently, Vertex announced that the FDA has accepted the marketing application of the Nav1.8 inhibitor VX-548 (Suzetrigine) and granted priority review qualification for the treatment of moderate to severe acute pain.

This is a major breakthrough in the field of analgesics and may subvert the competitive landscape of analgesics commercialization. Analgesics have always been valued by the medical community, both in academia and industry. And every pharmacology textbook and medicinal chemistry textbook used as a teaching material cannot avoid a classic drug: morphine. Whether it is its rigid structure of five fused rings or its analgesic and antitussive pharmacological effects, it is well known to every pharmacist. It is the pioneer of opioid analgesics.

There is no need to introduce the main defects of morphine. Its strong addictiveness makes it generally only used for pain relief in patients with advanced cancer. The development of analgesics with new pathways is urgent, and NaV1.8 is such an existence. It is well known that the sodium ion channel on the surface of the cell membrane is the basis for starting the ion potential, and the change of potential controls the neural pathway. The sodium ion channel is mainly composed of α and β subunits. If you can find a way to control the switch of the voltage base, you can find a way to change the neural pathway and inhibit pain. Among the α subunits, the subtypes related to pain are mainly NaV1.3, NaV1.7, NaV1.8, and NaV1.9, while only NaV1.8 and NaV1.9 are only expressed in peripheral sensory neurons and will not affect the sympathetic nerves that control key functions of the human body.

As long as you find a way to change the activation state of these two channels, you can lose the feeling of pain, which also makes it an important potential target for analgesia. The most important advantage of NaV1.8 over opioids is its non-addictive nature. As mentioned above, NaV1.8 is only expressed in peripheral neurons, so it does not affect the central nervous system and does not produce addiction problems similar to morphine.

From the perspective of drug development, the Phase III clinical trial of VX-548 has also progressed smoothly. At the end of January this year, Vertex announced the Phase III clinical data of VX-548 for the treatment of moderate to severe acute pain. The main clinical endpoints of this clinical trial are the time-weighted sum score of the difference in pain intensity within 48 hours (SPID48) and the digital pain rating scale (NPRS), and the scores on the scale represent a decrease in pain severity. This trial includes two parts: analgesia treatment for abdominal plastic surgery and hallux valgus correction, which is not only compared with placebo, but also with opioid analgesics.

In the abdominal plastic surgery trial, VX-548 performed very well in both key scale data when compared with placebo. In terms of SPID48 scores, the mean score of the VX-548 group was 118.4, while that of the placebo group was 70.1. In terms of the NPRS scale, the average time for the VX-548 group to drop by 2 points was 2 hours, while that of the placebo group was 8 hours; in the end, the NPRS scale of the VX-548 group dropped by 3.4, while that of the placebo group dropped by 2.3, achieving a very significant difference. However, in the control trial with opioids, neither the SPID48 nor the NPRS scale showed a better effect. For example, in the NPRS scale data, opioids finally dropped by 3.3, and the difference was not obvious.

In hallux valgus correction surgery, VX-548 also showed a significant difference in efficacy compared with placebo. For example, in terms of the difference in SPID48 scores, the mean score of VX-548 was 99.9, while that of the placebo group was 70.6. However, there was no significant advantage in the comparison with opioids. Overall, VX-548 has shown significant therapeutic effects in Phase III clinical trials. Although it has not shown an analgesic effect superior to that of opioid analgesics, it is already a leap forward in terms of acute analgesics in terms of non-addictiveness.

Vertex was founded in 1989 and listed on the Nasdaq in 1991. Although it cannot compare with MNCs such as Pfizer in terms of corporate lifespan, it can no longer be defined as "biotech". The performance of the pharmaceutical company in recent years can be described as a new bloom on an old tree. In November 2021, its market value was less than US$50 billion, but now it has a market value of US$130 billion. Vertex's fame is mainly due to its years of deep cultivation in the field of cystic fibrosis (CF). Its beginnings in the field of cystic fibrosis can be traced back to 2001, when Vertex acquired Aurora to obtain the cystic fibrosis pipeline, and the gears of fate began to turn. In 2011, Kalydeco (ivacaftor) was approved by the FDA for marketing. It is a synergist of CFTR protein and became the first effective drug for the treatment of CF. It was very popular and its sales in the first year reached 170 million US dollars.

However, Kalydeco can only treat a condition called gating mutation - there is enough protein on the membrane, but the channel is not open long enough to allow ions to pass through. This means that Kalydeco's design can only treat only 4% of patients, about 3,000 people worldwide, and Kalydeco has been confirmed to be only for adults and children six years old and above, reducing the number of patients to 2,400. The limitation of the number of indications has once again aroused Vertex's ambition to explore in this field. In 2015 and 2018, Vertex successively launched Orkambi and Symdeko, continuously expanding the coverage of drugs for the indication population.

What really made Vertex score the last goal in the CF field was its flagship commercial product Trikafta, and it is more famous for its current status as the top 1 in sales of rare disease drugs in the world. Trikafta is a compound preparation consisting of three drugs: Elexacaftor, Tezacaftor, and Ivacaftor. Its main function is to increase the efficacy of Ivacaftor in CF patients, that is, to further enhance the function of CFTR protein. In 2019, it took only three months from the submission of the application to FDA approval, and sales climbed at an astonishing rate. In 2020, its first full year on the market, sales reached US$3.864 billion. In 2021, this figure climbed to US$5.7 billion, ranking 16th in the global drug revenue rankings that year. By 2023, its revenue had reached US$8.945 billion, ranking 13th in the global drug revenue rankings that year, and it was also the only rare disease drug among the top 20 drugs.

At present, the patient population covered by Vertex's CF drug has increased from 4% at the beginning to 90%. This is a story of successful commercialization of a pharmaceutical company and a medical epic of the conquest of a rare disease. In 2016, the US FDA issued a warning to restrict the use of opioid analgesics; in 2017, the US Department of Health and Human Services (HHS) officially announced that opioid abuse has become a public health emergency. It was also at a similar time that Vertex's efforts in the field of analgesia gradually entered the public's field of vision.

But its development of NaV1.8 drugs has not been smooth sailing. Before VX-548, its other drug with the same target, VX-150, had failed. The drug began clinical research on VX-150 around 2018, but eventually stopped in clinical phase II due to excessive adverse reactions caused by excessive dosage. Another drug with the same target, VX-961, also stopped development after the end of phase I due to pharmacokinetic reasons. Ten years of drinking ice can hardly cool hot blood; dripping water wears away stone, but it takes time. Behind the launch of the blockbuster VX-548 is Vertex's ten years of hard work on this target. Now, the harvest day is finally approaching.

As a first-in-class, the commercial value of VX-548 is enough to amaze the market. According to Vertex's statement, it plans to request FDA approval of VX-548 for the treatment of moderate to severe acute pain within H2 2024. And its subsequent pipeline has greater room for indication expansion. VX-548's indication for diabetic peripheral neuropathy obtained positive data from Phase II clinical trials in December last year and reached the primary endpoint, and the clinical trial for lumbar radiculopathy is currently in Phase II. The huge indication space brings huge sales potential in the future. According to analysts at Wall Street investment bank Leerink, by 2032, VX-548 will generate $4.4 billion in sales for acute pain indications; it will generate $7 billion in sales for neuropathic pain indications - that is, snatching the market for the current traditional painkillers pregabalin and gabapentin in the United States. There are 86 million prescriptions for such drugs in the United States in 2023.

However, it is worth noting that both pregabalin and gabapentin are more addictive. In addition, in 2019, the FDA warned that patients with respiratory risk factors may experience serious respiratory problems when using gabapentin or pregabalin. These factors provide ample opportunities for the iteration of VX-548 in chronic pain. However, different institutions hold different views on whether it can overcome neuropathic pain. For example, analysts at Royal Bank of Canada Capital Markets said that the chronic pain market will be the key for Vertex to overcome. But the threshold is very high, and the corresponding results will not be clear until 2025.

Conservatively speaking, the forecast sales data given by Wall Street research firm Evaluateresearch is that VX-548 will reach US$2.9 billion in 2030. At present, the market space elasticity of the drug is very large, which also has a very large impact on Vertex's valuation. Now the key focus is on its overcoming of chronic pain.

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