World First KRAS Inhibitor Sales Plummeting?

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World First KRAS Inhibitor Sales Plummeting?

Amgen’s KRAS G12C inhibitor, Lumakras, received approval in 2021, marking a significant breakthrough in targeting KRAS mutations. However, Lumakras, as the pioneer in this field, is now facing increasing uncertainty along its path.

In the realm of groundbreaking drug development, revolutionary breakthroughs are rarely without challenges and uncertainties.

Recently, Lumakras has faced consecutive setbacks. Firstly, the FDA’s Oncologic Drugs Advisory Committee raised doubts about the reliability of confirmatory trials. Secondly, in the third quarter of this year, Lumakras’ sales saw a significant drop, reaching levels similar to its initial launch period, shedding light on more market-related issues.

Lumakras now stands on the edge of a precipice.

A Stagnant Market

RAS, the first identified human oncogene, was discovered in the 1960s. It can be categorized into three subtypes: KRAS, HRAS, and NRAS. Among these, KRAS is the most common and accounts for approximately 85% of oncogenic RAS mutations.

KRAS mutations are prevalent in various major cancers, such as lung cancer, colorectal cancer, pancreatic cancer, and biliary tract cancer. KRAS G12C mutations, in particular, constitute about 44% of all KRAS mutations. Consequently, KRAS has been a highly competitive target for pharmaceutical companies, with a particular focus on KRAS G12C.

However, for several decades, almost all attempts to develop targeted therapies against KRAS mutations ended in failure. The main challenge was the smooth, pocketless surface of the KRAS protein, making it difficult to design compounds that could effectively inhibit its activity. This led to the label of “undruggable target” for KRAS.

Over time, this stalemate was finally broken. In May 2021, the US FDA granted accelerated approval for Lumakras to treat locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with KRAS-G12C mutations who had received at least one prior systemic therapy.

Lumakras, heralded as the first global KRAS inhibitor, carried high expectations. It offered both new treatment options for patients and the promise of significant revenue growth for Amgen.

However, Lumakras seemed to hit a plateau right from the start.

World First KRAS Inhibitor Sales Plummeting?

Lumakras sales by quarter

Sales figures for Lumakras were $90 million in its first year on the market (May to December 2021). Breaking it down by quarter, it reached $36 million in the third quarter and $45 million in the fourth quarter, showing gradual growth.

Now, comparing it to 2022, the annual sales reached $285 million, a notable increase compared to the $90 million in sales for two quarters in 2021. However, when broken down by quarter, the results were concerning. In the first quarter of 2022, it achieved $62 million, the second quarter $77 million, the third quarter $75 million, and the fourth quarter $71 million. While it initially appeared to be on a growth trajectory, it began to decline in the third quarter.

Fast forward to 2023, and the trend is eerily similar. In the first quarter of 2023, Lumakras sales were $74 million, and in the second quarter, $77 million, with a year-on-year drop already evident in the second quarter.

However, history has a way of repeating itself, and the second half of 2023 saw a similar decline.

According to Amgen’s Q3 2023 financial report, Lumakras only generated $52 million in sales in the third quarter of 2023, a drop of approximately 31% year-on-year and about 32.5% compared to the previous quarter.

The sales of innovative drugs depend on various factors, including sales capabilities, production capacity, insurance coverage, and doctor/patient acceptance. Amgen attributes Lumakras’ sales decline to ongoing reimbursement negotiations in France and inventory issues.

Comparing Lumakras’ sales in different regions over the past two quarters, in the second quarter, the US generated $50 million in sales, while other regions contributed $27 million. In the third quarter, US sales were $48 million, and other regions only amounted to $4 million.

These figures raise two key issues. Firstly, the US market has not shown significant growth, and secondly, apart from France, commercialization in other countries where Lumakras is available has been less than satisfactory. According to Amgen, the $23 million impairment primarily relates to the French market, indicating that Lumakras has only achieved sales of $3 million in other European Union countries, the UK, Japan, and similar nations.

World First KRAS Inhibitor Sales Plummeting?

Countries where Lumakras is approved

For Lumakras, which was expected to lead the way as the world’s first KRAS inhibitor, this market performance is undoubtedly disappointing.

Adding to the woes, Lumakras faced a significant setback in terms of regulatory approval.

A Potential Delisting

Lumakras received accelerated approval based on a phase II clinical trial called CodeBreaK 100. The results showed that Lumakras achieved an objective response rate (ORR) of over 37.1%, progression-free survival (PFS) extended to 6.8 months, and disease control rate (DCR) of 80.6%. However, the therapy came with a high rate of treatment-related adverse events (TRAE), with severe AE occurring in 29.6% of patients.

For a balanced risk-benefit profile, the FDA required Amgen to conduct a confirmatory trial.

Thirty months after Lumakras’ approval, the FDA’s Oncologic Drugs Advisory Committee held a hearing for the phase III confirmatory trial, CodeBreak 200.

The outcome was 2 votes in favor and 10 votes against. Experts on the FDA’s Oncologic Drugs Advisory Committee found the primary endpoint, which was evaluated independently and blinded, for PFS to be unreliable.

While this result should not be simplistically interpreted as Lumakras being ineffective for patients, it does cast a shadow of uncertainty over Lumakras’ ultimate fate. The final verdict will be revealed on December 14.

Considering that the main reason for the experts’ high rate of opposition was related to issues with the trial design, rather than the potential of KRAS inhibitors, there is still hope for this class of drugs.

Therefore, from another perspective, Amgen’s stumble may create opportunities for competitors to catch up.

The Future of KRAS Inhibitors

Mirati’s adagrasib, the second KRAS inhibitor to gain FDA approval (granted accelerated approval in late 2022), has faced a slow climb in sales, generating $19.7 million in total sales in the first half of this year.

Comparing the two approved KRAS inhibitors, both Lumakras and adagrasib have shown similar effectiveness. However, adagrasib has a higher rate of adverse reactions compared to Lumakras.

With the uncertain future of Lumakras, adagrasib is neither first in class nor second, and both drugs have experienced slow sales growth. This situation opens up opportunities for potential competitors in the field.

SUMMARY

KRAS G12C inhibitors are a breakthrough for KRAS targets. Two drugs have been launched successively. However, judging from the current performance, there are more regrets. One of the inseparable reasons is that the clinically accessible population is not big.

Therefore, for the more common mutation sites such as G12D and G13C, it is particularly important to think about what Lumakras’ breakthrough, Lumakras’ clinical design flaws, and Lumakras’ success or failure can bring to future drugs.

Going back to the KRAS G12C target competition itself, when domestic pharmaceutical companies continue to rush onto the track, when Lumakras, the pioneer, has moved step by step to the edge of the cliff, how can the latecomers achieve self-certification, and who can take the responsibility to prove the KRAS competition? Talking about the golden burden, behind the “undruggable” nature of KRAS inhibitors, someone still needs to complete the answer.