Tony Hagen is senior managing editor for The Center for Biosimilars®.
Years ahead of patent expirations for programmed death-1 (PD-1) inhibitors, biosimilar companies have begun focusing on these targeted drugs.
The marketing of programmed death (PD) inhibitors in the treatment of cancer got off the ground in 2014 with the launches of pembrolizumab (Keytruda) and nivolumab (Opdivo), first indicated for patients with melanoma and then expanded to multiple indications, including non–small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, and esophageal carcinoma.
The first biosimilars for these products may be years off, as exclusivity protections remain in force for the originator products, but a handful of companies have announced interest in developing biosimilars for these agents, most recently NeuClone of Redfern, Australia, which in an interview with The Center for Biosimilars® said the groundwork for these biosimilars is well underway.
“We’re feeling quite confident about these molecules and feeling pretty positive about the outlook moving forward,” said company strategic analyst Thomas Wakim.
The PD-1 Mechanism
Pembrolizumab and nivolumab are both PD-1 inhibitors. PD-1 is a "checkpoint" protein on immune cells that alerts them not to attack cells that express PD-L1. Some cancer cells express PD-L1, which enables them to “switch off” an immune system response. Monoclonal antibodies such as pembrolizumab and nivolumab block this signaling between PD-1 and PD-L1 and thereby reinforce the immune system response to tumor cells.
Even in late-stage cancers, these drugs have demonstrated effectiveness across tumor types. Recently, pembrolizumab was granted FDA approval for unresectable or metastatic solid tumors with high tumor mutational burden in patients who have exhausted other options for treatment. The FDA decision was based on an overall response rate of 29% (95% CI, 21%-39%), which included a 4% complete response rate and a 25% partial response rate. More than half of patients (57%) had response durations of 12 months or longer.
Besides their many indications for use as monotherapy, pembrolizumab and nivolumab have also shown promise in combination therapy, which extends their utility as cancer-fighting tools. In May 2020, nivolumab was approved in combination with ipilimumab and platinum chemotherapy as a frontline treatment for patients with metastatic or recurrent non–small cell lung cancer. The combination therapy demonstrated superior overall survival (OS) vs chemotherapy alone. Median OS was 14.1 months in the combination arm vs 10.7 months for chemotherapy (HR, 0.69; 96.71% CI, 0.55-0.87; P = .0006).
The increasing utility of these agents across cancer settings and their effectiveness have contributed to increasing market value for the originator companies.
Pembrolizumab, a Merck product, had worldwide sales of $11.1 billion in 2019, up 55% from $7.2 billion the year before. A glance at quarterly sales revenue indicates that earnings continue to grow strongly for this product. Pembrolizumab sales were $3.4 billion in the second quarter of 2020, up 29% from $2.6 billion in the comparable year-ago quarter.
Nivolumab had $7.2 billion in 2019 worldwide revenues, up 7% from $6.7 billion the prior year. The second-quarter 2020 sales total was $1.7 billion, up 9% from the previous year.
Power of Numbers
Such numbers help to explain the attraction companies such as NeuClone have for developing biosimilars of these products. “From a really commercial standpoint, they seem like quite good opportunities for developing biosimilars and trying to capture a share of the market they represent,” Wakim said. Because the cost of these originator drugs has been going up, there is tremendous value potential for patients in the downward effect on pricing that biosimilars can exert, he added. Although drug regimens may differ, estimates of the cost of a year’s course of pembrolizumab or nivolumab range as high as $150,000.
“We see from a biosimilar standpoint that there’s a great opportunity to introduce cheaper, more affordable versions of these drugs to really bring down that health care expenditure and allow many more patients around the world to gain access to what are incredibly effective and beneficial oncology treatments,” he said.
Multiple patents for nivolumab exist, but one estimate suggests that patent exclusivity in the United States for this product could end in 2027. Neuclone is positioning itself for market launch of both products by the end of this decade. “We envision that probably toward the late 2020s—at least, that’s what the originator companies have reported publicly. And that gives us ample time to conclude our preclinical work on these biosimilars and, in the coming years, enter phase 1 and possibly phase 3 clinical trials,” Wakim said.
As for target markets, NeuClone aims to obtain regulatory approvals for its pembrolizumab and nivolumab biosimilars in both the United States and the European Union. Not only are patients and providers more accepting of biosimilars in these markets, but also the strength of regulatory approvals from the FDA and European Medicines Agency (EMA) can give NeuClone “leverage” to obtain marketing approvals in other regions of the world, Wakim said. “We envision that with an approval, say, in Europe from the EMA, it would allow us to relatively smoothly bring our products into the Australian market through the [Therapeutic Goods Administration].”
Among companies with announced intent to bring PD-1 inhibitors to market is Mabpharm of Taizhou, China, which has indicated it has the nivolumab biosimilar candidate CMAB819 approved for clinical trials.
In addition, Celltrion of Incheon, Republic of Korea, has reportedly begun work on a biosimilar version of pembrolizumab.