BTK Inhibitors' Next Level: Advancing into Autoimmune Diseases – Lupeng Pharmaceutical Files IPO
Hansoh Pharma
Pharmaceutical Research, Production, and Sales
Since the launch of AbbVie's Ibrutinib in 2013, a total of six Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have been approved worldwide (including the first-generation Ibrutinib, second-generation Acalabrutinib, Zanubrutinib, Tirabrutinib, and Orelabrutinib; and third-generation Pirtobrutinib), achieving tremendous success in the field of hematological tumors. Meanwhile, beyond the field of oncology treatment, BTK inhibitors are seeking new growth opportunities, such as...AutoimmuneSexually transmitted diseases.
Since autoimmune diseases typically involve abnormal selection and activation of autoreactive B cells and subsequent autoantibody production, each B cell has a unique antigen receptor, the B cell receptor (BCR), which recognizes specific antigens to activate the B cell. BTK is a crucial signaling protein that directly links BCR signaling to B cell activation, proliferation, and survival, making BTK a promising therapeutic target for autoimmune diseases. Multiple pharmaceutical companies have already positioned themselves in this field, including Hansoh Pharma, which recently reached a collaboration.
RMB 729 million: Hansoh Pharma doubles down on BTKi autoimmune track
Recently, Hansoh Pharma and Guangzhou Lupeng Pharmaceutical reached a cooperation agreement, under which Hansoh will obtain all non-oncology indications of LP-168 in China (includingChinaHong Kong,ChinaMacao andChinaTaiwan), as well as the research and development, registration, production, and commercialization rights. Meanwhile, Hansoh Pharma will pay Loupeng Pharma an upfront payment, along with potential milestone payments for R&D, registration, and sales-based commercialization totaling no more than 729 million RMB, as well as tiered royalties of up to double digits based on future net product sales.
LP-168 is a small molecule BTK inhibitor (BTKi) that covalently binds to and irreversibly inhibits the activity of wild-type BTK. When a mutation occurs at the BTK C481 site, it can reversibly bind to and inhibit BTK activity through non-covalent interactions. Currently, Lupeng Pharmaceutical has initiated multiple clinical studies on LP-168. In May 2024, LP-168 received breakthrough therapy designation from the CDE for the treatment of relapsed or refractory (R/R) non-germinal center B-cell type (non-GCB) diffuse large B-cell lymphoma (DLBCL).
In the autoimmune field, LP-168's proposed indications for development mainly focus on autoimmune diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), which have already demonstrated good safety and efficacy potential in preclinical studies.
At the same time, Hansoh Pharma also holds an open attitude towards BD. The acquisition of LP-168 this time is expected to strengthen its layout in the autoimmune field.
MNC's Layout in the BTKi Autoimmune Track
Currently, multiple pharmaceutical companies have been strategically focusing on BTK inhibitors for autoimmune disease applications, with indications primarily concentrated in MS and NMOSD.
MS is an autoimmune disease that occurs in the central nervous system, caused by the immune system attacking the myelin sheath. The inflammation and tissue damage induced by the disease disrupt the normal functions of the brain, optic nerves, and spinal cord. Approximately 2.5 million people worldwide are affected, with the primary age of onset being between 20 and 40 years old. Currently, there is no curative therapy available.
Currently, no BTK inhibitors have been approved for the MS indication. In terms of clinical progress, Merck's Evobrutinib and Roche's Fenebrutinib are among the leaders.
Merck's Evobrutinib is a highly selective oral BTKi capable of crossing the blood-brain barrier, designed to inhibit B-cell proliferation and the release of antibodies/cytokines without directly affecting T-cell function.
In the Phase II clinical trial, the results showed that after three and a half years of Evobrutinib treatment: the group of patients receiving a dose of 75 mg (twice daily) of Evobrutinib maintained an annualized relapse rate (ARR) at a low level of 0.13. Throughout the study, the average EDSS (a measure of disability), as well as lesion activity detected by MRI, remained consistently low. Moreover, levels of neurofilament light chain (NfL), an important biomarker associated with nerve cell damage, continued to decrease compared to baseline.
However, in the subsequent Phase III clinical study, the results showed that compared with oral teriflunomide, Evobrutinib did not achieve the primary endpoint of reducing ARR in patients with relapsing MS. Ultimately, Evobrutinib unfortunately stumbled in the MS field. However, its overall safety and tolerability profile was consistent with the previously reported results of the Phase II trial. Merck stated that it will complete a comprehensive evaluation of the EVOLUTION clinical trial data and present and release specific results in the future.
Roche's Fenebrutinib is an investigational oral, reversible, and non-covalent BTK inhibitor. Preclinical data show that Fenebrutinib is potent and highly selective, with 130 times greater selectivity for BTK than for other kinases. Additionally, Fenebrutinib is a dual inhibitor of B-cell and microglial activation, which may reduce MS disease activity and disability progression.
In the Phase II clinical trial, Fenebrutinib reduced T1 and T2 lesions in patients' brains detected by gadolinium-enhanced imaging by over 90%. Meanwhile, biomarker tests showed that Fenebrutinib can cross the blood-brain barrier and reach concentrations in the brain sufficient to directly inhibit inflammation. After 12 weeks of continuous treatment, the average fenebrutinib concentration was 43.1 ng/mL. The levels of fenebrutinib in the brain and central nervous system may be adequate to reduce MS disease activity and progression in patients.
NMOSD is a rare autoimmune inflammatory demyelinating disease of the central nervous system, primarily affecting the optic nerves and spinal cord. NMOSD is characterized by high recurrence and severe disability, with most patients experiencing serious visual impairment or limb dysfunction, leading to a significant disease burden.
Hengrui Medicine's Edralbrutinib is a highly effective, novel, irreversible second-generation oral BTKi, which was recently granted Orphan Drug Designation by the FDA for the treatment of NMOSD.
Besides MS and NMOSD, Novartis’ orally administered BTKi Remibrutinib has opted for the indication of Chronic Spontaneous Urticaria (CSU), which is an autoimmune condition that causes temporary inflammatory hyperemia and tissue edema in the skin, mucous membranes, and blood vessels due to various factors, significantly impacting quality of life. In the two Phase III studies for CSU, REMIX-1 and REMIX-2, Remibrutinib achieved positive results, meeting all primary and secondary endpoints, and may become the first novel CSU drug in nearly a decade.
Since the advent of BTK inhibitors, the field has remained intensely competitive. Facing fierce competition in the area of hematological tumors, many newcomers have embarked on differentiated development and are making significant advances.AutoimmuneIn the field of autoimmune diseases. Currently, there are over 20 BTK inhibitors being explored in the autoimmune disease sector, but the exploration of BTKi in the autoimmune track is still in its early stages, with significant challenges such as safety and efficacy yet to be overcome.
Reference Source:
1.https://www.businesswire.com/news/home/20221025005142/en.
2.Late-breaking data for Roche’s BTK inhibitor fenebrutinib show brain penetration and significant reduction in lesions in patients with relapsing multiple sclerosis.
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