By Anna Rose Welch, Chief Editor, Biosimilar Development
Over the past six months of quarantine, many of you have clearly been taking advantage of the (slight) slow-down in normal life and using that time to flex your writing muscles. As a result, the biosimilar industry has benefited from a wealth of diverse biosimilar publications. Whether it be biosimilar misinformation, unsuccessful regulatory filings, or biosimilar quality attributes, there has been something for everyone. In addition to these topics, I was happy to read one publication in Future Oncology entitled, “Rituximab Biosimilars In Hematologic Malignancies: The Need For A Real-World Approach” by Pilar Nava-Nadar, co-authored by Ahmed Shelbaya and Chadi Nabhan.
Earlier in 2020, I had a conversation with Nabhan, chairman of the Precision Oncology Alliance for Caris Life Sciences, and adjunct professor in the Department of Clinical Pharmacy and Outcomes Sciences at the University of South Carolina. In two previous, quite popular articles, he shared his thoughts on hospital biosimilar usage and the role of biosimilars in value-based care. Following publication of the Future Oncology paper, I reconnected with Nabhan to hear his thoughts on how biosimilar rituximab will integrate into the standard of care (especially in the face of novel lymphoma therapies) and how he envisions a real-world approach for rituximab and other oncology biosimilars taking shape.
A Closer Look At Rituximab On The Market
Despite the pandemic, the biosimilar space in 2020 has come alive, thanks to the arrival of biosimilars for the Roche blockbuster trio (Avastin, Herceptin, and Rituxan). In fact, Sanford Bernstein biosimilar analyst Ronny Gal went so far as to say that we’re now entering “The Golden Age of Biosimilars.” Given Nabhan’s publication, I wanted to single out rituximab and hear his thoughts on the role rituximab biosimilars in particular will play in the future treatment of certain cancers.
As Nabhan briefly explained, rituximab, an anti-CD20 chimeric mAB, is used in the front-line and relapsed setting of all B-cell non-Hodgkin lymphomas, such as follicular lymphoma, chronic lymphocytic leukemia (CLL), and diffuse large B-cell lymphoma, among other subtypes. The antibody is also approved by the FDA for several autoimmune indications, including rheumatoid arthritis, Wegener’s Granulomatosis, microscopic polyangiitis, and (adult) Pemphigus Vulgaris.
In this industry, we are acutely aware that competitive market dynamics have been intense — especially in cases where originator life-cycle management strategies have garnered significant market share. When it comes to Rituxan, there are a couple of key players to watch in the anti-CD20 treatment space. For one, Roche has developed a next-gen version, Rituxan Hycela, which is a combination subcutaneous treatment of rituximab and hyaluronidase. (This new version does not necessarily eliminate the need for IV rituximab, however, as the FDA approval stipulates the subcutaneous option can only be used following one initial dose of IV-administered rituximab.)
In recent years, the FDA has also approved two anti-CD20 originators, including Novartis Arzerra and Roche’s own Gazyva — the latter of which analysts expected to be Roche’s answer to Rituxan’s patent expiration. Though Gazyva is also approved for CLL and follicular lymphoma, like Rituxan, a few years ago the treatment failed to best Rituxan plus chemo in a Phase 3 trial in diffuse large B-cell lymphoma. This put a bit of a crimp into the company’s plans to siphon away Rituxan’s market share, though analysts have pegged Gazyva to make the biggest dent in the larger follicular lymphoma market. In fact, GlobalData forecasts some impressive sales growth for Roche’s Gazyva, with global sales expected to increase from $564 million in 2019 to $2 billion in 2026.
Nabhan also called attention to the promise of CAR-T therapies, bi-specific antibodies, and conjugate antibodies which are currently being developed for the treatment of lymphomas —mainly in the relapsed setting. However, though they may impact the uptake of biosimilar rituximab to some extent, he does not anticipate they will diminish Rituxan’s or its biosimilars’ standings as a standard of care. In fact, like many of these legacy oncology mAb treatments, there is still a lot to be learned about rituximab’s mechanism of action and why it works best in certain patient subsets. Similarly, as one 2018 publication in the Frontiers of Oncology points out, because the novel anti-CD20 medicines have different dosages, it’s been difficult to declare any of them a new “best-in-class” option in comparison to rituximab.
As the authors say best, “The gaps in knowledge surrounding rituximab make assessing next generation anti-CD20 therapies and rituximab biosimilars a challenging goal, providing opportunities for improvement as the relative efficacies of these new mAbs are evaluated.”
Hence the importance and opportunity of further real-world analysis of rituximab biosimilars.
Rituximab In The “Real World” Clinical Setting
As an oncologist, Nabhan pointed out that real-world evidence (RWE) and real-world data (RWD) are critical for any biologic — novel and biosimilar alike.
“I am a big believer in the value of RWE and RWD because many drugs are approved based on randomized-controlled trials that involve several hundred patients,” he explained. “This does not provide an adequate look into how the drug performs in the broader patient population.” In fact, as the authors shared in their paper, 92-95 percent of oncology patients are treated outside of clinical trials. Similarly, the elderly and those with comorbidities are more likely to receive treatment in the real-world setting.
But in the biosimilar realm, Nabhan anticipates that RWE — especially starting out — will be critical to assuage oncologists’ concerns over the concept of extrapolation. In cases where rituximab could lead to a cure — such as diffuse large B-cell lymphoma — physicians less comfortable with the regulatory approval data of biosimilars may be more cautious given that each rituximab biosimilar’s comparative efficacy trial was only carried out in follicular lymphoma. (The same concerns are still present in physician populations outside of oncology, as well. A Cardinal Health survey recently reviewed that the concepts of extrapolation and interchangeability remain a concern for 45 percent of rheumatologists — despite the fact they do trust the FDA review and approval process.)
Outside of providing ongoing safety and efficacy information in all approved indications, Nabhan also singled out patient-reported outcomes (PROs) as an increasingly important form of RWE in the oncology sector. Though there remain several challenges in integrating PROs into real-world studies (as outlined in the paper), these outcomes can aid in patient/caregiver decision making and quality assessments for healthcare systems, as well as lead to an overall improvement of patient care. Nabhan pointed in particular to the work of Dr. Ethan Basch of the University of North Carolina; a 2017 JAMA research letter penned by Basch revealed that integrating PROs into routine oncology patient care led to increased patient survival compared to patients who were not given an opportunity to self-report symptoms. (However, it’s important to note that this paper focused on patients with solid tumors as opposed to lymphoid malignancies.)
Given CMS’ ongoing efforts to shift from volume-based to value- and quality-based prescribing, such data can be incredibly important in positioning a biosimilar as highly similar to its reference product and as a safe and clinically beneficial standard of care, especially as newer (higher priced) agents continue to arrive on the market. Given the amount of biosimilar competition we have begun to see in oncology, Nabhan expressed optimism that patient insights into the drug’s performance could serve as a valuable product differentiation factor, as well.
“Incorporating PROs into real-world studies allows us as physicians and manufacturers to better understand the true impact of our treatments on patients from the patients themselves,” he added. “This is an ongoing, evolving discussion, and one I personally hope to see developing further in the future.”
In addition to addressing remaining clinical uncertainties, biosimilar makers must also prioritize providing data around the cost-effectiveness of their biosimilar products in comparison to the originator and the biosimilar’s potential impact on a clinic’s bottom line. This could be especially important for the IV-administered rituximab biosimilars that will be going up against a subcutaneous originator.
“Looking at the impact of your product on a practice’s bottom line — especially as the oncology sector continues to progress toward value-based care — is critical,” Nabhan confirmed. For example, on the surface, a subcutaneous option may seem like the most patient-friendly, efficient, and cost-effective model. However, as Nabhan explained, this option could be less efficient if it requires any additional chair time for monitoring, office visits for follow-ups, or a trained home-nurse to assist in the administration.
“There are opportunities to determine a biosimilar — or an originator’s — impact on clinical chair and nursing time and hospitalization rates. Whenever we look at the economic modeling of biologics, we must not overlook the totality of healthcare resources necessary to successfully deliver the treatment, as well.”