Breakthrough Clinical Results
Genentech announced positive results from the Phase III ALLEGORY study of Gazyva in adults with systemic lupus erythematosus (SLE) on standard therapy. The study met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in SLE Responder Index 4 (SRI-4) at one year compared to standard therapy alone. All key secondary endpoints were also met, with no new safety signals identified. Gazyva has the potential to be a transformative new standard of care for people affected by SLE worldwide. If approved, Gazyva would be the first anti-CD20 therapy for SLE to directly target B cells.
Key Highlights
- Phase III ALLEGORY study met primary and all key secondary endpoints with Gazyva in SLE patients.
- Gazyva has the potential to be a transformative new standard of care for up to 3.4 million people affected by SLE worldwide.
- If approved, Gazyva would be the first anti-CD20 therapy for SLE to directly target B cells.
- Positive results follow recent FDA approval and positive EU CHMP opinion for Gazyva in lupus nephritis.
Incidence and Prevalence
Latest Global Estimates of Systemic Lupus Erythematosus Incidence and Prevalence
Systemic lupus erythematosus (SLE) is a disease of multifactorial etiology with marked disparities in rates worldwide. Recent epidemiological studies provide comprehensive insights into its global distribution.
Global Incidence
According to a 2023 study, the global SLE incidence is estimated at 5.14 per 100,000 person-years (1.4 to 15.13), representing approximately 0.40 million newly diagnosed people annually. The incidence shows significant gender disparity: - For women: 8.82 per 100,000 person-years (2.4 to 25.99), equating to 0.34 million women newly diagnosed annually - For men: 1.53 per 100,000 person-years (0.41 to 4.46), representing 0.06 million men newly diagnosed annually
A 2022 meta-analysis of low-and-middle income countries (LMICs) revealed a pooled incidence of 5 cases per year per 100,000 (95% CI: 2-8). By region, the American region showed a higher pooled incidence of 10 per 100,000 (95% CI: 0-14).
Geographic variations are substantial: - Highest incidence: North America at 23.2 per 100,000 person-years - Lowest incidence: Africa and Ukraine at 0.3 per 100,000 person-years - Poland, USA, and Barbados have the highest estimates globally
A 2024 nationwide study in China found the childhood-onset SLE incidence rate was 3.97 per 100,000 person-years (95% CI: 3.93-4.01), with a declining trend observed over the 5-year study period.
Global Prevalence
The global SLE prevalence is estimated at 43.7 per 100,000 persons (15.87 to 108.92), representing approximately 3.41 million people worldwide. Gender differences are pronounced: - In women: 78.73 per 100,000 persons (28.61 to 196.33), affecting 3.04 million women - In men: 9.26 per 100,000 persons (3.36 to 22.97), affecting 0.36 million men
Racial disparities are evident: - For Caucasian populations: 81 per 100,000 persons - For Black populations: 212 per 100,000 persons
In LMICs, SLE prevalence varied from 3.2 to 159 per 100,000 persons, with a pooled prevalence of 103 per 100,000 (95% CI: -17 to 224). By WHO regions, the American region showed a prevalence of 300 per 100,000 (95% CI: -200 to 900), while the Western Pacific region had 36 per 100,000 (95% CI: 35-37).
Country-specific data shows significant variation: - Sweden: 46 to 85 per 100,000 depending on definition strictness - South Korea: Increased from 21.25 per 100,000 in 2005 to 35.45 per 100,000 in 2015 - United Arab Emirates, Barbados, and Brazil have the highest SLE prevalence globally
Notably, epidemiological data on SLE are lacking for 79.8% of countries worldwide, and SLE occurs more frequently in high-income countries.
The female to male ratio ranges from 6:1 to 10:1, with age-specific variations. Cutaneous variants of lupus erythematosus are 2-3 times more frequent than SLE itself.
Key Unmet Needs and Target Populations in Systemic Lupus Erythematosus
Despite significant advances in understanding SLE pathophysiology and optimizing care, numerous unmet needs persist. Early diagnosis remains challenging for many patients despite new classification tools. Lupus nephritis (LN) continues to be a frequent and difficult to treat complication causing high morbidity and mortality, with 20-35% of patients suffering from relapse or ineffective treatment.
Current treatment challenges include: * Standard treatments (anti-inflammatory drugs, corticosteroids, antimalarials, immunosuppressants) are not always effective * Need for minimizing glucocorticoids while maintaining disease control * Refractory lupus nephritis management despite multiple therapeutic options * Medication intolerance is frequent in lupus nephritis patients * Broad immunosuppression leaving patients vulnerable to infections
Key target populations include: * Patients with refractory lupus nephritis not achieving renal remission with conventional treatments * Childhood-onset SLE (cSLE) patients, with belimumab now approved for children >5 years * Patients with severe/refractory cSLE, particularly with lupus nephritis * Patients with lupus nephritis classes III and IV requiring induction therapy * ANA or anti-dsDNA-positive SLE patients with moderate skin and musculoskeletal symptoms * Patients with severe interferon-mediated inflammatory disease * Asian patients with SLE targeted in specific regional recommendations * Patients at high risk for organ dysfunction needing early intervention * Elderly patients with lupus nephritis and refractory discoid lupus erythematosus * Patients with hard-to-treat manifestations * Patients with SLE during pregnancy * Patients with comorbidities
Research priorities include: * Further disentangling SLE susceptibility and pathogenesis * Identifying more accurate biomarkers * Implementing new ways to measure disease activity * Developing new trial modalities for drug development * Optimizing currently available therapeutics
Emerging therapeutic approaches addressing unmet needs include biological agents with high specificity, JAK inhibitors, CAR-T therapy for severe/refractory cases, anti-CD20 monoclonal antibodies, novel agents like telitacicept for refractory LN, and canakinumab (IL-1β antagonist).
There are also significant unmet needs in antimalarial (AM) prescription, with only 37.9% of physicians adjusting doses for renal failure, one-third not following American screening guidelines for AM retinal toxicity, and 40.9% starting retinal screening from the first treatment year.
In pediatric patients, most treatments are off-label drugs based on inadequately powered studies or consensus guidelines. A substantial disease burden exists in Australian patients, with almost one-third considered to have moderate to severe disease based on medication use.
Despite recent approvals of belimumab, anifrolumab, and voclosporin, additional therapeutic options are needed as a definitive cure remains elusive.
Genentech's Pipeline Drug Indications
Genentech has a diverse pipeline of drugs targeting various therapeutic areas and disease indications. Their development portfolio spans multiple disease categories with several promising candidates in different stages of clinical development.
Cancer Indications
Genentech has a strong oncology focus with drugs targeting:
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Breast cancer: Herceptin (trastuzumab) was launched in 1998, particularly effective when combined with doxorubicin and paclitaxol. Additional breast cancer therapies include trastuzumab emtansine and trastuzumab deruxtecan, which are antibody-drug conjugates.
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Colorectal cancer: Bevacizumab (Avastin) has shown promising efficacy in phase II clinical trials for metastatic colorectal cancer. When added to chemotherapy (5-fluorouracil plus leucovorin), it resulted in a higher objective response rate (40% versus 17%), longer time to disease progression (9.0 versus 5.2 months), and longer median survival time (21.5 versus 13.8 months).
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Non-small cell lung cancer (NSCLC): Targeted with erlotinib (Tarceva), an EGFR-selective inhibitor of tyrosine kinase. NSCLC is also one of the most frequently studied tumor sites in combination with radiation therapy.
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Basal cell carcinoma (BCC): Vismodegib (Erivedge) is undergoing phase II clinical trials for advanced BCC. This drug was discovered by Genentech in collaboration with Curis Inc. and suppresses Hh signaling by binding to smoothened.
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Medulloblastoma (MB): Phase I clinical trials with vismodegib have shown an objective response in patients with MB.
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Ovarian cancer: Vismodegib is in phase II clinical trials for this indication.
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Head and neck cancer: The most frequently studied (26%) in radiation therapy combinations, where Genentech is the most active sponsor (22% of pharmaceutical sponsorship).
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Acute myeloid leukemia: Venetoclax in combination with hypomethylating agents is being evaluated for elderly patients who are ineligible for standard induction therapy.
Hematological Malignancies
- Non-Hodgkin's lymphoma (NHL): Rituxan (rituximab), a genetically engineered chimeric murine/human monoclonal antibody directed against CD20, was initially approved for relapsed or refractory low-grade or follicular NHL. It was the first monoclonal antibody approved by the FDA for a cancer indication in 1997.
Immunology and Neurology
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Multiple sclerosis: Rituxan (rituximab) is being evaluated for relapsing-remitting multiple sclerosis (RRMS).
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Autoimmune diseases: Rituxan is also used to treat various immune-mediated and autoimmune diseases.
Ophthalmology
- Neovascular age-related macular degeneration (nAMD): Genentech has FDA-approved anti-VEGF therapy (ranibizumab) for this indication.
Genentech's pipeline demonstrates their commitment to developing targeted therapies across multiple therapeutic areas, with a particular strength in oncology and immunology. Their approach often involves precision medicine, as exemplified by Herceptin, which was the first anticancer drug whose use is decided based on the status of the HER2 gene amplification/HER2 protein over-expression.