Chronic Lymphocytic Leukemia Market To Grow Despite Biosimilar Wave
Executive Summary
The chronic lymphocytic leukemia market is set to increase in size over the next decade despite an anticipated influx of biosimilars, new research by Datamonitor Healthcare finds. AbbVie/J&J's Imbruvica will remain the leading product, but the need for safe and effective therapies for relapsed and refractory CLL patients remains.
The chronic lymphocytic leukemia (CLL) market has been pegged to grow over the next nine years, with sales of major drugs in the US, Japan and the five major EU markets almost doubling from $3.5bn in 2016 to $6.1bn in 2025, Datamonitor Healthcare reports.
Between 2016 and 2025, the CLL market will see current therapies, such as AbbVie Inc./Johnson & Johnson's Imbruvica (ibrutinib) and AbbVie/Roche's Venclexta (venetoclax), increasing their sales and uptake, alongside the approval of several new pipeline therapies. Adding to the mix will be the arrival of biosimilars of mainstay anti-CD20 products like Roche/Biogen's Rituxan (rituximab) and generic versions of other current treatments.
CLL Drug Classes
PI3K inhibitors: Zydelig (idelalisib) and generic idelalisib, duvelisib
Anti-CD20s: Arzerra (ofatumumab), Rituxan (rituximab), biosimilar rituximab, Gazyva (obinutuximab) and ublituximab
BCL-2 inhibitors: Venclexta (venetoclax)
BTK inhibitors: Imbruvica (ibrutinib), acalabrutinib
DNA alkylators: Treanda/Bendeka (bendamustine) and generic bendamustine
CLL is characterized by the build-up of malignant B lymphocytes in the blood, bone marrow and lymph nodes and is the most common form of leukemia. Specific cell surface markers and immunophenotypes distinguish CLL from other B-cell lymphomas and CLL B-cells usually express the antigens CD5, CD19, CD20, and CD23, and surface immunoglobulin. Within CLL, there are high-risk subgroups of patients with particular genetic alterations, such as deletions in chromosomes 11q and 17p that are linked with the loss of the ATM (ataxia-telangiectasia mutated) and p53 genes, and lead to rapid disease progression.
Patients often do not receive treatment immediately following diagnosis of early-stage CLL but undergo a period of 'watchful waiting'. The standard first-line therapy once treatment is appropriate is then a chemotherapeutic regimen containing Rituxan, particularly the standard-of-care for first-line systemic therapy for late-stage CLL of fludarabine, cyclophosphamide and Rituxan (FCR). The DNA alkylator bendamustine and Rituxan regimen (BR) is the second most popular therapy in this treatment setting.
The heterogeneity of CLL combined with varying fitness levels of patients make treatment decisions complicated, Datamonitor Healthcare notes. Treatment algorithms are usually tailored to each individual patient with late-stage CLL, who may have a resistant or refractory form of the disease. The current standards of care for relapsed or refractory CLL are single-agent Imbruvica, and the combination of Gilead's PI3K inhibitor, Zydelig (idelalisib) and Rituxan.
Other currently approved drug classes for CLL include the Bcl2 inhibitors (see box).
Climbing Sales, Expanding Market
With the prevalence of the disease set to increase with the aging population across the seven major markets, Datamonitor Healthcare says the uptake of CLL products overall is anticipated to follow suit. But Imbruvica, will remain the lead pharmacological therapy, with sales expected to climb from $1.9bn in 2016 to $3.4bn in 2025. Imbruvica is forecast to gain increasing uptake as a monotherapy in the first-line setting and as a component of future drug combination regimens.
Since its initial approval in 2014 in the relapsed setting, the first Bruton's tyrosine kinase (BTK) inhibitor product Imbruvica has risen swiftly to dominate the market due to a series of successful label expansions. Imbruvica is currently approved in all lines of therapy, as well as for treating high-risk CLL patients with 17p deletions or p53 mutations and has established itself as an important component of CLL therapy against more established CLL branded therapies, such as Rituxan, in a relatively short period of time. Indeed, prescribing trends from a Datamonitor Healthcare primary survey indicate that Imbruvica is one of the top first-line therapies for CLL, and is the leading pharmacological therapy for relapsed/refractory CLL.
The strong growth for Imbruvica will come despite the anticipated approval of pipeline drugs in 2018, particularly AstraZeneca PLC/Acerta Pharma BV's rival BTK inhibitor acalabrutinib and another anti-CD20 MAb from LFB Biotechnologies SAS/TG Therapeutics Inc., ublituximab.
DMHC analyst Dominique Fontanilla said, "Current promising Phase III pipeline drugs [ublituximab and acalabrutinib] are not expected to contribute to market growth in a significant way as they are targeting initial approvals in the relapsed setting for high-risk patients with 17p deletions or p53 mutations, which will likely restrict their initial uptake." Another pipeline product, Infinity Pharmaceuticals Inc./Verastem Inc.'s duvelisib is not expected to pose much of a threat as its development in CLL will be limited both geographically and in terms of target patient population.
Overall, BTK inhibitor sales are expected to increase from $1.9bn in 2016 to $3.9bn in 2025 with Imbruvica making up 87% of those sales (see Figure 1).
Dr Brian T. Hill, Cleveland Clinic
But there is a chink in Imbruvica's amour, notes one expert, Dr Brian T. Hill from Cleveland Clinic. He said that though ibrutinib's overall toxicity and efficacy was favorable, some patients stop using the drug due to side effects like atrial fibrillation or because they develop resistance against it. There are other BTK inhibitors in development, including acalabrutnib, that do not have the same type of toxicity or incidence of atrial fibrillation, he said.
"Some patients on ibrutinib develop resistance due to mutations in the binding site of the BTK protein that ibrutinib binds to, in these cases there are BTK inhibitors in development that may overcome that and there are other classes of drugs, including venetoclax and idelalisib, which may work," Hill explained.
The newest novel agent for CLL, the Bcl2 inhibitor Venclexta, is expected to give Imbruvica some competition as it expands in relapsed and first-line CLL treatment in combination with other products in 2018-2019. Its sales are anticipated to jump from $25.9m in 2016 to $255m in 2025. However, AbbVie and J&J will look to expand Imbruvica for first-line CLL in combination with Roche/Biogen's CD20 Gazyva (obinutuzumab) in 2018, which may give it another step up in the sales ladder.
Gilead Sciences Inc. is forecasted to expand the label of its PI3K inhibitor Zydelig (idelalisib), making it a part of drug regimens in relapsed CLL, starting with the BR regimen in the US and five EU markets in 2017. However, Zydelig will be at a slight disadvantage to its competitors, due to safety issues and increased rate of serious and fatal adverse events. Physicians are going to be more inclined to choosing an alternative therapy, leaving Zydelig as an option for later lines of treatment.
Though it possesses the most products, the CD20 class is expected to rake in less than the BTK class and will see sales rise slightly from $1.2bn in 2016 to $1.5bn in 2025 despi8te biosimilar competition, Datamonitor Healthcare believes
Biosimilar & Generics Wave
The greatest threat to market leaders in the CLL market will be the entrance of biosimilars and generics, Fontanilla said, however, these cheaper alternatives will not bring the market growth to a halt over 2016-25.
During the forecast period, patents protecting CLL products including the anti-CD20s, Rituxan, Genmab AS/Novartis AG's CD20 Arzerra (ofatumumab), and Gazyva, Teva Pharmaceutical Industries Ltd.'s DNA alkylator Treanda (bendamustine) and Zydelig are set to expire.
Roche's succession planning for Rituxan comprises Gazyva and Venclexta and the launch of a subcutaneous formulation of Rituxan in the US in 2017. Gazyva will also face biosimilar erosion itself later in 2024 but DMHC said that Roche would not lose out in the CLL space – its revenue expected to hover around $1.2bn over the forecast period.
Ahead of the expected generic bendamustine arrival around 2019, Teva has taken precautions and produced a rapid-infusion formulation of bendamustine, Bendeka. The company stopped distributing the liquid formulation of Treanda since 30 March 2016 and though the lyophilized formulation of Treanda will still be available, DMHC predicts that a fair chunk of Treanda’s patient share in the US will transfer to Bendeka by Q2 2017, protecting Teva against potential major sales erosion.
More Effective Therapies Needed
Despite numerous therapies and a number in the clinic, the need for safe and effective treatment for relapsed and refractory CLL grows. With the development of drugs for relapsed and refractory CLL, initial response rates have improved but majority of affected patients relapse again and need further treatment. DMHC notes that outcomes and response rates for patients with relapsed and refractory CLL is poor, with those carrying cytogenetic abnormalities in the 11q and 17p chromosomes experiencing rapid disease progression, and patients with 17p-deleted CLL not responding well to traditional chemotherapy.
Though there are therapies showing clinical efficacy in 17p-deleted, TP53-mutated and fludarabine-refractory CLL, further development is required to boost safety and tolerability as current pipeline agents may be linked to high levels of toxicity and higher risk of immunosuppression, making them unsafe for unfit and elderly patients.
Hill flagged up another area for further investigation: "There are lot of new drugs for CLL including ibrutinib, venetoclax and idelalisib, however the big question in the field is how to sequence these new treatments and whether or not combinations are going to be more useful than using these drugs alone."
Data from Datamonitor Healthcare. For more information on the research covered in this article, click here