慢性淋巴球性白血病 (CLL) 治療藥
Chronic Lymphocytic Leukemia (CLL)
本報告提供慢性淋巴球性白血病 (CLL) 治療藥市場相關調查分析，市場預測，治療，流行病學，上市藥，開發平台等相關的系統性資訊。
Chronic lymphocytic leukemia (CLL) is a disorder where the bone marrow produces B lymphocytes that are morphologically mature but immunologically less mature. These lymphocytes do not fight infection as well and survive longer than normal lymphocytes, and therefore accumulate in the bone marrow, peripheral blood, and lymph nodes. CLL diagnosis is usually confirmed by evaluating lymphocytic morphology, by the presence of a specific immunophenotype (CD5-positive and CD23-positive B cells), and by a monoclonal B lymphocyte count in the peripheral blood of at least 5,000 cells per microliter for a minimum of three months.
Datamonitor Healthcare estimates that in 2018, there were 86,900 incident cases of chronic lymphocytic leukemia (CLL) worldwide, and expects that number to increase to 91,000 incident cases by 2027.
The CLL treatment paradigm has changed significantly over the past five years, with targeted therapies such as Bruton's tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors displacing chemotherapy-based treatments for most patients who have CLL.
Monotherapy with the BTK inhibitor Imbruvica is the preferred front-line therapy and induces durable remissions in the majority of patients. However, most of these remissions are only partial responses, and long-term treatment is required which can be complicated by adverse toxic effects (cardiac arrhythmias, fungal infections, and bleeding) and the emergence of resistance.
Imbruvica patents have expiration dates ranging from 2026 to 2036; however, the FDA gave Zydus final approval for generic Imbruvica (70mg or 140mg) in April 2021. In March 2021, Johnson & Johnson and Zydus entered into a confidential settlement agreement that likely delays the launch of generic Imbruvica. Imbruvica has regulatory exclusivity for first-line treatment of CLL patients without a 17p deletion through March 2023.
Calquence, a second-generation BTK inhibitor, has been positioned as more tolerable than Imbruvica, and is typically used as monotherapy for front-line patients who cannot tolerate Imbruvica. This improved safety profile was confirmed in ELEVATE-RR, a Phase III head-to-head comparison of Calquence versus Imbruvica in relapsed/refractory (R/R) patients. While the ELEVATE-RR trial showed non-inferiority rather than superiority with regard to progression-free survival (PFS), the trial established that patients treated with Calquence had a significantly lower incidence of atrial fibrillation compared to patients treated with Imbruvica. As physician familiarity with Calquence grows, its use in the front-line setting will grow too.
Brukinsa, another second-generation BTK inhibitor, is currently approved in China and is under development in the US and EU for both treatment-na簿ve and R/R CLL. While Brukinsa has demonstrated promising safety and efficacy, the drug will face significant competition as it is positioned to be the third BTK inhibitor approved for CLL.
Venclexta combined with the anti-CD20 rituximab is the preferred regimen for patients who relapse after a BTK inhibitor. In the R/R setting, the Venclexta regimen is given for two years and induces deep minimal residual disease (MRD)-negative remissions. However, resistance clones can emerge and clinical relapses can occur, especially in high-risk patients. Venclexta combined with Gazyva is approved as a 12-month fixed-length regimen for front-line CLL based on the CLL14 trial. If long-term follow-up data from CLL14 show durable remissions, Venclexta may see further uptake in the first-line setting.
The small pool of newly diagnosed, younger, fit patients with low-risk CLL (ie mutated IGHV) are often treated with Rituxan combined with fludarabine and cyclophosphamide (FCR). This chemoimmunotherapy regimen usually leads to remissions lasting more than 10 years.
Various Phase III trials are evaluating fixed-duration Imbruvica and Venclexta regimens in the front-line setting. GLOW is a Phase III trial evaluating Imbruvica combined with Venclexta versus chlorambucil combined with Gazyva. Imbruvica monotherapy is administered for three cycles, followed by Imbruvica combined with Venclexta for 12 cycles. An NCI-sponsored Phase III trial, A041702, is evaluating the triple combination of Imbruvica, Venclexta, and Gazyva versus Imbruvica and Gazyva as a comparator. After 15 cycles, patients in the experimental arm who are bone marrow MRD-negative can stop therapy, while those that are not MRD-negative will continue Imbruvica monotherapy until disease progression.
Zydelig is a PI3K inhibitor and is approved in combination with rituximab for the treatment of R/R CLL in both the US and EU, and is typically used in the third-line setting. In March 2016, the FDA and EMA issued public health advisories for Zydelig, noting an increased rate of serious adverse events and deaths in trials evaluating Zydelig combinations.
Copiktra is a PI3K inhibitor approved in the US as monotherapy for the treatment of R/R CLL after at least two prior therapies, and is currently under regulatory review in the EU. Copiktra's FDA label includes several black box warnings for fatal/serious infections, diarrhea, cutaneous reactions, and pneumonitis. Furthermore, the label notes that discontinuation was seen in 36% of patients in the Phase III DUO trial.
Gazyva is a third-generation anti-CD20 antibody developed as a replacement for Rituxan and is most often used in combination with Venclexta for newly diagnosed patients. Gazyva is expected to lose market exclusivity in 2025.
Rituxan is used in various combinations including with Venclexta and Zydelig in the R/R setting, and as part of the FCR combination for certain niche segments of front-line patients. Roche has developed a subcutaneous formulation of Rituxan, but both the intravenous and subcutaneous formulations face increasing competition from intravenous Rituxan biosimilars.
Treanda/Bendeka is typically used either as monotherapy or in combination with an anti-CD20 antibody either for first-line or R/R CLL. In both settings, current NCCN guidelines list Treanda/Bendeka as an "other recommended therapy", and the shift away from chemotherapy/chemoimmunotherapy is expected to lead to a declining market share for Treanda/Bendeka.
A rolling BLA submission has been completed for Ukoniq, a PI3K inhibitor, combined with ublituximab, an anti-CD20 monoclonal antibody, for first-line and R/R CLL. If approved, the Ukoniq combination (TG-1303) will mostly be used in the third-line or later setting where it will compete with Zydelig and Copiktra, with safety favoring Ukoniq. A Phase III trial initiated in 2021 (ULTRA-V) is comparing a fixed-length regimen of TG-1303 combined with Venclexta to TG-1303 given until disease progression.
Breyanzi, a CD19-directed autologous CAR-T therapy, is the only CAR-T therapy being evaluated in a pivotal trial for CLL. Breyanzi's outlook will become clearer once safety and efficacy results from the pivotal trial are available, but CAR-T therapy offers the promise of an effective treatment for R/R high-risk CLL patients and for patients who have failed the three main targeted therapies of BTK inhibitors, Venclexta, and PI3K inhibitors.
Pirtobrutinib and MK-1026 are next-generation BTK inhibitors that reversibly inhibit both wild-type and C481-mutant BTK. These inhibitors have shown good proof-of-concept results in patients resistant to covalent BTK inhibitors due to a C481 mutation. In terms of safety, there were no observations of atrial fibrillation or major bleeding, both of which are adverse events typically associated with the covalent BTK inhibitor class. If results from the dose expansion are positive, these agents may be positioned to seek accelerated approval for patients who fail a BTK inhibitor.
Key recent events include the approval of Calquence in Europe (November 2020) and Japan (January 2021), and Phase III readouts for Calquence (ELEVATE-RR trial), Ukoniq + ublituximab (UNITY-CLL), and Brukinsa (ALPINE).
Key upcoming catalysts for the next 12 months include approval of Ukoniq + ublituximab, and pivotal trial readouts for Brukinsa (SEQUOIA) and Imbruvica + Venclexta (GLOW).
The overall likelihood of approval of a Phase I CLL/SLL asset is 12.1%, and the average probability a drug advances from Phase III is 68.4%. CLL/SLL drugs, on average, take 9.7 years from Phase I to approval, compared to 9.6 years in the overall oncology space.