Lilly, GSK, Vir co-develop neutral and antibody combination therapies; FDA approves the first innovative oral lupus nephritis therapy

▎The content team editor of WuXi PharmaTech approves the first innovative treatment for oral lupus nephritis, Aurinia Pharmaceuticals, recently announced that the U.
S.
FDA has approved Luppynistm (voclosporin) to be marketed in combination with background immunosuppressive therapy to treat active lupus nephritis (LN) Adult patients.

The press release stated that Lupkynistm is the first oral therapy for LN approved by the FDA.

This is also the second new drug for lupus nephritis approved by the US FDA in less than two months after Benlysta (belimumab) was approved at the end of December last year.

Lupus nephritis is one of the most serious and common complications of autoimmune disease systemic lupus erythematosus (SLE).

The patient’s kidney damage leads to proteinuria and/or hematuria, as well as decreased renal function and increased serum creatinine levels.

It causes irreversible kidney damage and significantly increases the risk of kidney failure, cardiac events, and death.

Lupkynistm is a potential "best-in-class" new calcineurin inhibitor (CNI).

It stabilizes kidney podocytes by inhibiting calcineurin, blocking IL-2 expression and T cell-mediated immune response.

Compared with the traditional CNI, it shows a more predictable pharmacokinetic and pharmacodynamic relationship.

▲Lupkynistm molecular structure (picture source: Ed (Edgar181) / Public domain) The approval of Luppynistm is supported by global clinical trial data, including two key clinical studies-Phase 3 clinical trial AURORA and Phase 2 clinical trial AURA -LV.

The results of a pivotal phase 3 clinical trial involving 357 LN patients showed that Lupkynistm achieved a complete renal response rate of 40.
8%, compared with 22.
5% in the control group (p<0.
001).

At the same time, Lupkynistm reached all secondary endpoints and also showed excellent efficacy in the pre-identified subgroup analysis.

▲Lupkynistm reached the primary and secondary endpoints in the pivotal phase 3 clinical trial (picture source: reference [2]) Roche's long-acting bispecific antibody phase 3 clinical results are positive, and a single injection for 4 months to treat patients with specific macular degeneration recently , Roche announced that its bispecific antibody faricimab has achieved positive top-line results in two global phase 3 clinical trials of TENAYA and LUCERNE in the treatment of patients with neovascular age-related macular degeneration (nAMD).

Faricimab is a bispecific antibody that targets both VEGF-A and Angiopoietin-2 (Ang-2).

nAMD affects approximately 20 million people worldwide and is the main cause of blindness among people aged 60 and above.

The current standard treatment is injection of drugs that inhibit vascular endothelial growth factor (VEGF), which can significantly reduce vision loss caused by nAMD.

However, VEGF is not the only factor that causes the occurrence and development of diseases.

And nAMD patients receiving anti-VEGF monotherapy usually need to go to the ophthalmologist to receive eye injections every month.

The press release states that faricimab is the first bispecific antibody under investigation designed for the eye.

It targets two different pathways, Ang-2 and VEGF-A.
Ang-2 and VEGF-A destroy the stability of blood vessels and lead to the formation of new leaky blood vessels and increase inflammation, thereby affecting vision.

By blocking these two pathways, faricimab aims to stabilize blood vessels, which may lead to better long-term vision results for people with retinal diseases.

▲Schematic diagram of the structure of Faricimab (picture source: Roche official website) TENAYA and LUCERNE are two identical randomized double-blind, global phase 3 clinical studies that evaluated the efficacy and safety of faricimab compared with a control of VEGF inhibitor activity in 1329 patients with nAMD .

The primary endpoint of the study was the average change in the best corrected visual acuity (BCVA) score from baseline to week 48.

Both studies met their primary endpoints, and the visual acuity results of patients receiving faricimab reached the standard of non-inferiority compared with the active control group (one injection every 8 weeks).

Nearly half (45%) of the patients in the two studies received faricimab every 16 weeks in the first year.
This is the first time that an ocular injection for the treatment of nAMD has achieved such a long durability in a phase 3 clinical trial.

AbbVie JAK inhibitor approved for the treatment of psoriatic arthritis and ankylosing spondylitis AbbVie (AbbVie) recently announced that the European Commission (EC) has approved its JAK inhibitor Rinvoq (upadacitinib) for extended indications for treatment Adult patients with active psoriatic arthritis (PsA).

These patients have an intolerance or inadequate response to one or more rheumatoid arthritis therapies (DMARDs) that alter the course of the disease.

Rinvoq can be used as monotherapy or in combination with methotrexate.

Rinvoq is also approved for the treatment of adult patients with active ankylosing spondylitis (AS) who are not as effective as conventional therapies.

This is the first time this JAK inhibitor has been approved to treat these two types of patient groups.

Psoriatic arthritis is a systemic inflammatory disease with symptoms in multiple parts of the body.

Inflammation of the immune system in patients with psoriatic arthritis can lead to skin lesions, joint pain, fatigue, and stiffness associated with psoriasis.

Ankylosing spondylitis is a chronic, inflammatory musculoskeletal disease that mainly affects the spine.
It is characterized by debilitating symptoms such as pain, restricted mobility, and structural damage. Despite advances in therapies to treat these two diseases, there are still many patients whose symptoms have not been sufficiently relieved.

Rinvoq is a selective small molecule inhibitor of JAK1 that is taken orally once a day.

Previously, the FDA has approved its marketing for the treatment of adult patients with moderate to severe active rheumatoid arthritis.

In addition, it is also undergoing clinical research in multiple other inflammatory indications, including Crohn's disease, ulcerative colitis, and atopic dermatitis.

These two approvals are supported by the results of three clinical trials.

In two phase 3 clinical trials of SELECT-PsA1 and SELECT-PsA2, Rinvoq reached the primary endpoint in adult patients with active psoriatic arthritis with poor efficacy of DMARD.

That is, compared with placebo, the ACR20 response was significantly improved at the 12th week.

Compared with the common therapy adalimumab, Rinvoq also reached the standard of non-inferiority.

Compared with the placebo group, patients receiving Rinvoq also showed greater improvement in physical function and skin symptoms.

 In the Phase 2/3 clinical trial SELECT-AXIS1, Rinvoq is used to treat adult patients with ankylosing spondylitis who have not received biological DMARD treatment.

The results of the trial showed that Rinvoq reached the primary endpoint, and the patient’s Spondyl Arthritis International Association (ASAS) 40 response assessment was significantly improved compared to placebo.

In the treatment of non-small cell lung cancer, TROP2-targeted ADC clinical results are positive.
Recently, AstraZeneca and Daiichi Sankyo announced at the World Lung Cancer Conference (WCLC) 2020 two antibody pairs jointly developed by the two parties.
The positive results of the combination drug (ADC) datopotamab deruxtecan (DS-1062) and Enhertu in the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC). Datopotamab deruxtecan is a research ADC targeting TROP2, and Enhertu is an ADC targeting HER2 that has been approved.

Lung cancer is one of the leading causes of cancer deaths, accounting for about one-fifth of all cancer deaths worldwide.

80-85% of lung cancers belong to NSCLC.

Currently, no therapies targeting TROP2 or HER2 have been approved for the treatment of NSCLC.

Test results of antibody conjugate drugs targeting TROP2 TROP2 is a transmembrane glycoprotein that is overexpressed in many cancer types.

The high expression of TROP2 is related to the poor overall survival and disease-free survival of several solid tumors.

In NSCLC patients, TROP2 expression is observed in up to 64% of adenocarcinomas and up to 75% of squamous cell carcinomas.

Datopotamab deruxtecan is a potential "best-in-class" antibody conjugate drug designed using Daiichi Sankyo’s DXd antibody coupling technology platform.
It uses a tetrapeptide linker that can be selectively cleaved near the tumor to target The monoclonal antibody to TROP2 is linked to a topoisomerase inhibitor.

▲Introduction to Datopotamab deruxtecan (DS-1062) (picture source: Reference [7]) In the phase 1 clinical trial named TROPION-PanTumor01, a total of 159 patients with advanced or metastatic NSCLC received different doses of datopotamab deruxtecan (4 mg/kg, 6 mg/kg or 8 mg/kg).

These patients had received more than 3 pre-treatments, including platinum-containing chemotherapy (94%) or immunotherapy (84%).

When the median follow-up time was 7.
4 months, the objective response rate (ORR) determined by the independent review committee was between 21% and 25%, the disease control rate was between 67% and 80%, and the median progression-free survival The period is between 4.
3 months and 8.
2 months. ▲Efficacy data of the phase 1 clinical trial of Datopotamab deruxtecan (picture source: reference [6]) Based on the existing efficacy and safety results, AstraZeneca and Daiichi Sankyo will start a registered phase 3 clinical trial to test the treatment of datopotamab deruxtecan Efficacy of NSCLC patients.

Results of Enhertu's Phase 2 Clinical Trial In the Phase 2 clinical trial called DESTINY-Lung01, patients with metastatic NSCLC who highly express HER2 received Enhertu treatment.

These patients received an average of 3 pre-treatments, including platinum-containing chemotherapy (91.
8%) or immunotherapy (73.
5%).

At a median follow-up of 6.
1 months, Enhertu achieved an ORR of 24.
5% and a disease control rate of 69.
4%.

The median progression-free survival was 5.
4 months.

Eli Lilly, GSK, and Vir collaborate to develop neutralizing antibody combination therapy.
Recently, Eli Lilly and Company, Vir Biotechnology, and GlaxoSmithKline (GSK) jointly announced that they have reached a partnership to address low-risk mild to moderate levels.
The combination of two neutralizing antibody therapies is evaluated in COVID-19 patients.

Eli Lilly has expanded its ongoing BLAZE-4 trial to evaluate the effectiveness of a combination therapy consisting of bamlanivimab (LY-CoV555) and VIR-7831 (also known as GSK4182136).

The press release pointed out that this unique collaboration marks the first time that neutralizing antibodies from different companies have been combined to explore potential therapeutic results.

Bamlanivimab is a neutralizing antibody that directly targets the spike protein of the new coronavirus, designed to block the virus from attaching and entering human cells.

Bamlanivimab was developed in cooperation with Eli Lilly and AbCellera and has received FDA Emergency Use Authorization (EUA) for the treatment of patients with mild to moderate COVID-19 who are at high risk of progression to severe COVID-19 and/or hospitalization.

VIR-7831 is a monoclonal antibody with a dual mechanism of action.

In preclinical trials, the antibody showed its ability to neutralize the new coronavirus by binding to an epitope on the new coronavirus shared with SARS-CoV-1.

This epitope is highly conserved, which may make escape mutants more difficult to produce.

Moreover, the modification of the Fc end of the antibody not only allows it to block the virus from entering healthy cells, but also activates the immune system and has the potential to eliminate infected cells.

WuXi AppTec’s content team charted the treatment of non-small cell lung cancer, and Amgen’s KRAS inhibitor achieved 80.
6% disease control.
Recently, Amgen announced its research KRAS G12C inhibitor sotorasib (AMG 510), which contains 126 cases The latest results from a pivotal Phase 2 clinical trial in patients with advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutations.

This is the first time the company has announced the efficacy results of this clinical trial after a follow-up period of more than one year.

NSCLC accounts for 80%-85% of all lung cancers, and most patients (66%) have advanced or metastatic disease at the time of initial diagnosis.

KRAS G12C is one of the most common driver mutations in NSCLC.

Patients with KRAS G12C mutant NSCLC who have failed first-line treatment have limited options, and the current treatment outcome is not ideal.

The remission rate of these patients with second-line treatment is about 9-18%, and the median progression-free survival is about 4 months.

Sotorasib developed by Amgen is the first KRAS G12C inhibitor to enter the clinical development stage.
It is currently being studied in a wide range of clinical projects.
In just over two years, the sotorasib clinical project has also established a deep clinical data set.
It has been used to treat more than 600 patients in studies of 13 tumor types.

It has been granted a breakthrough therapy designation by the US FDA, and Amgen has submitted a new drug application (NDA) for sotorasib to the US FDA at the end of last year.

▲Sotorasib molecular structure (picture source: User: Edgar181, Public domain, via Wikimedia Commons) In a key phase 2 clinical trial called CodeBreaK 100, patients with advanced non-small cell lung cancer with KRAS G12C mutation received once a day, Sotorasib was treated orally at a dose of 960 mg.

81% of these patients had received platinum-containing chemotherapy and PD-1/PD-L1 inhibitor treatment and their disease continued to progress.

The results of the trial showed that at a median follow-up time of 12.
2 months, sotorasib achieved a confirmed objective response rate (ORR) of 37.
1% and a disease control rate of 80.
6%, including 3 cases of complete remission and 43 cases of partial remission.

The median duration of remission was 10 months, and the median progression-free survival was 6.
8 months.

Note: This article is intended to introduce medical and health research, not to recommend treatment options.

If you need guidance on treatment plans, please go to a regular hospital for treatment.

Reference: [1] FDA Approves Aurinia Pharmaceuticals' LUPKYNIS™ (voclosporin) for Adult Patients with Active Lupus Nephritis.
Retrieved January 23, 2021, from https:// ] Aurinia Presentation at JPM 2021.
Retrieved January 23, 2021, from https://d1io3yog0oux5.
cloudfront.
net/_d5224235ef1d27ef939d1c33666b318d/auriniapharma/db/239/1388/presentation/Aurinia-Presentation-CorpDeck-FINicima faricima_JPM.
pdf[ meets primary endpoint in two global phase III studies and shows potential to extend time between treatments up to 16 weeks for people with neovascular age-related macular degeneration.
Retrieved January 25, 2021, from https:// releases/med-cor-2021-01-25.
htm[4] European Commission Approves AbbVie's RINVOQ™ (Upadacitinib) for the Treatment of Psoriatic Arthritis and Ankylosing Spondylitis.
Retrieved January 25, 2021, from https://news.
abbvie.
com/news/press-releases/european-commission-approves-abbvies-rinvoq-upadacitinib -for-treatment-psoriatic-arthritis-and-ankylosing-spondylitis.
htm[5] Lilly, Vir Biotechnology and GSK announce first patient dosed in expanded BLAZE-4 trial evaluating bamlanivimab (LY-CoV555) with VIR-7831 (GSK4182136) for COVID-19.
Retrieved January 27, 2021, from https://investor.
lilly.
com/news-releases/news-release-details/lilly-vir-biotechnology-and-gsk-announce-first-patient-dosed[6 ] Datopotamab deruxtecan and Enhertu show promising early clinical activity in patients with advanced non-small cell lung cancer.
Retrieved January 29, 2021, from https:// cancer.
html[7] R&D Day 2020.
Retrieved January 29, 2021, from https:// Amgen's Investigational KRAS G12C Inhibitor Sotorasib Demonstrated Rapid, Deep And Durable Responses In Previously Treated Patients With Advanced Non-Small Cell Lung Cancer.
Retrieved January 28, 2021, from https:// kras-g12c-inhibitor-sotorasib-demonstrated-rapid-deep-and-durable-responses-in-previously-treated-patients-with-advanced-non-small-cell-lung-cancer-301217636.
htmlhtmlhtmlcom/files/investors/library/materials/2020/pdf/RD%20Day%202020_E.
pdf[8] Amgen's Investigational KRAS G12C Inhibitor Sotorasib Demonstrated Rapid, Deep And Durable Responses In Previously Treated Patients With Advanced Non-Small Cell Lung Cancer.
Retrieved January 28, 2021, from https:// -patients-with-advanced-non-small-cell-lung-cancer-301217636.
htmlcom/files/investors/library/materials/2020/pdf/RD%20Day%202020_E.
pdf[8] Amgen's Investigational KRAS G12C Inhibitor Sotorasib Demonstrated Rapid, Deep And Durable Responses In Previously Treated Patients With Advanced Non-Small Cell Lung Cancer.
Retrieved January 28, 2021, from https:// -patients-with-advanced-non-small-cell-lung-cancer-301217636.
htmlcom/news-releases/amgens-investigational-kras-g12c-inhibitor-sotorasib-demonstrated-rapid-deep-and-durable-responses-in-previously-treated-patients-with-advanced-non-small-cell-lung- cancer-301217636.
htmlcom/news-releases/amgens-investigational-kras-g12c-inhibitor-sotorasib-demonstrated-rapid-deep-and-durable-responses-in-previously-treated-patients-with-advanced-non-small-cell-lung- cancer-301217636.
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