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Aduhelm (aducanumab) approved for the treatment of Alzheimer’s disease.

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On June 7, 2021, the U.S. Food and Drug Administration approved Aduhelm (aducanumab) for the treatment of Alzheimer’s disease. Developed by Biogen, aducanumab is a human IgG1 antibody that targets anti-amyloid b. Biogen licensed the worldwide rights to aducanumab from Neurimmune in 2007, and has collaborated with Eisai on the global development and commercialization of aducanumab since 2017.

The late-stage development program for Aduhelm consisted of two Phase 3 clinical trials. One study met the primary endpoint, showing reduction in clinical decline. The second trial did not meet the primary endpoint.  In all studies in which it was evaluated, Aduhelm reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion.  The reduction in amyloid  plaque is considered a surrogate for a reduction in clinical decline. Aduhelm was approved using FDA’s accelerated approval pathway, which can be based on the drug’s effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. A post-approval trial to verify that the drug provides the expected clinical benefit is required.

Need help keeping up to date on US and EU approvals?

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format.

EUA issued for anti-SARS-CoV-2 sotrovimab

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On March 27, 2021, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for sotrovimab (VIR-7831; GSK4182136) for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progression to severe COVID-19, including hospitalization or death. The EUA was issued to GlaxoSmithKline.

Sotrovimab, a human anti-SARS-CoV2 antibody, is being evaluated in a Phase 1/2/3 randomized, double-blind, placebo-controlled clinical trial in non-hospitalized adults with mild-to-moderate COVID-19 symptoms and a positive SARS-CoV-2 test result. The EUA is based on an interim analysis of results for 583  patients in the study, 291 and 292  of whom received sotrovimab or placebo, respectively, within five days of onset of COVID-19 symptoms. The primary endpoint was progression of COVID-19 (defined as hospitalization for greater than 24 hours for acute management of any illness or death from any cause) through day 29. Hospitalization or death occurred in 21 (7%) patients who received placebo compared to 3 (1%) patients treated with sotrovimab.

Sotrovimab is administered as a 500 milligram single dose given intravenously over 30 minutes by health care providers.

Prior to the authorization of sotrovimab, FDA issued EUAs for the treatment of mild-to-moderate COVID-19 for two combinations of anti-SARS-CoV-2 monoclonal antibodies. The combination of casirivimab and imdevimab was authorized in November 2020 and the combination of bamlanivimab and etesevimab was authorized in February 2021. In addition, Celltrion’s anti-SARS-CoV-2 antibody regdanvimab (CT-P59; Regkirona) received authorization in South Korea in February 2021.

More than 20 additional anti-SARS-CoV-2 monoclonal antibodies are undergoing evaluation in clinical studies. Of these, 7 monotherapies or combinations are in late-stage clinical studies, including ADG20 (Adagio Therapeutics) and AZD7442 (AstraZeneca). The Antibody Society will continue to track these investigational antibodies and report progress in the future.

Amivantamab granted FDA approval for non-small cell lung cancer

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On May 21, 2021, U.S. Food and Drug Administration approved Rybrevant (amivantamab-vmjw) as the first treatment for adult patients with non-small cell lung cancer (NSCLC) whose tumors have specific types of genetic mutations: epidermal growth factor receptor (EGFR) exon 20 insertion mutations. Rybrevant received Priority Review and Breakthrough Therapy designation for this indication.

Amivantamab (JNJ-61186372; Janssen Pharmaceutical Companies of Johnson & Johnson) is a human, low-fucose IgG1-based bispecific antibody targeting EGFR and mesenchymal epithelial transition factor (MET) that was created using Genmab’s DuoBody technology. Amivantamab has been shown to function through multiple mechanisms of action in preclinical models of NSCLC with EGFR exon 20 insertion driver mutations, which cause tumor cells to be insensitive to EGFR tyrosine kinase inhibitors.

The efficacy of amivantamab was evaluated in a study of 81 patients with non-small cell lung cancer and EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. In the trial population in which all patients received the drug, the overall response rate was 40% and the median duration of response was 11.1 months, with 63% of patients having a duration of response of 6 months or more.

FDA’s review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For review of amivantamab, the FDA collaborated with the Brazilian Health Regulatory Agency and United Kingdom’s Medicines and Healthcare products Regulatory Agency.

Need help keeping up to date on US and EU approvals?

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format.

Antibody therapeutics for melanoma

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May is Melanoma Awareness Month, with awareness campaigns kicking off on the first Monday (May 3rd in 2021). Melanoma is caused by cancerous melanocytes, which are cells in the epidermis that normally make a pigment, melanin, that protects other skin cells from damaging sun rays. The American Cancer Society (ACS) estimates the lifetime risk for developing the disease is ~ 2.6% (1 in 38) for whites, and 0.6% (1 in 167) for Hispanics, and 0.1% (1 in 1,000) for Blacks. Overall, melanoma is more common in men, and the risk of melanoma increases with age. The ACS’ data suggest that ~ 106,110 new melanomas will be diagnosed (~62,260 in men and 43,850 in women) and ~ 7,180 people may die of the disease in the United States during 2021.

Approved antibody therapies for melanoma

Three antibody therapeutics (ipilimumab, nivolumab, pembrolizumab)  that target the immune checkpoints CTLA-4 (CD152) or programmed cell death protein 1 (PD-1, CD279) are approved for melanoma.

  • YERVOY (ipilimumab), which targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), is indicated for the treatment of unresectable metastatic melanoma in adults and pediatric patients (12 years and older) and adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.
  • KEYTRUDA (pembrolizumab), which targets PD-1, is indicated for the treatment of patients with unresectable or metastatic melanoma, and for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.
  • OPDIVO (nivolumab), which targets PD-1, is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression, including following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, and for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Combination therapy was shown to be superior to monotherapy with these checkpoint inhibitors in the Phase 3 Checkpoint study, which evaluated nivolumab monotherapy or nivolumab combined with ipilimumab versus ipilimumab monotherapy in patients with previously untreated unresectable or metastatic melanoma. The overall survival (OS) at 5 years was 52%, 44% and 26% in the nivolumab-plus-ipilimumab, nivolumab monotherapy, and ipilimumab monotherapy groups, respectively. However, Grade 3 or 4 treatment-related adverse events occurred more frequently in patients who received combination therapy (59%, 23%, and 28% of patients in the nivolumab-plus-ipilimumab, nivolumab, and ipilimumab treatment groups, respectively).

Investigational antibody therapies for melanoma

While the antibody therapeutics that target CTLA-4 and PD-1 have benefited melanoma patients, biopharmaceutical companies are developing novel antibody therapeutics that target other immune checkpoints such as LAG-3 or use different mechanisms of action.

  • Bristol-Myers Squibb is developing relatlimab (BMS-986016), which is a human IgG4 antibody targeting LAG-3 on T cells, thereby restoring effector function of exhausted T cells. Primary results from the Phase 2/3 RELATIVITY-047 (CA224-047) trial evaluating the fixed-dose combination of relatlimab and Opdivo (nivolumab) versus Opdivo alone in patients with previously untreated metastatic or unresectable melanoma indicated that the trial met its primary endpoint of progression-free survival.
  • Philogen  S.p.A. is developing Nidlegy, which is composed of two single-chain variable fragment (scFv)-based immunocytokines that target extra-domain B of fibronectin (L19IL2 + L19TNF combination), as neoadjuvant intralesional treatment for melanoma patients with locoregional disease. Two randomized, controlled Phase 3 registration trials for intralesional application of Nidlegy as a neoadjuvant followed by surgery + eventual adjuvant treatments (standard of care) and compared to standard of care are currently ongoing in Europe (PIVOTAL; NCT02938299) and in the USA (Neo-DREAM; NCT03567889) in patients with fully resectable stage IIIB/C melanoma.
  • Immunocore Ltd is developing tebentafusp, which comprises a high- affinity T cell receptor specific to a peptide sequence from the gp100 antigen, which is presented on melanoma tumor cells by HLA-A2, fused to an anti-CD3 single chain antibody fragment. In a Phase 3 study, tebentafusp demonstrated a statistically significant and clinically meaningful improvement in OS as a first-line treatment in metastatic uveal melanoma.  Tebentafusp has been granted Breakthrough Therapy Designation, Fast Track designation and orphan drug designation by the FDA and Promising Innovative Medicine designation under the UK Early Access to Medicines Scheme for metastatic uveal melanoma. Immunocore will be working with the FDA to complete submission of a BLA for tebentafusp in the third quarter of 2021.

The Antibody Society continuously collects data for antibody therapeutics in the commercial clinical pipeline. We will provide updates on the antibody therapeutics being evaluated for melanoma in future posts.

Need help keeping up to date on US and EU approvals?

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format.

Loncastuximab tesirine granted first approval by FDA for large B-cell lymphoma

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On April 23, 2021, the  US Food and Drug Administration (FDA) granted accelerated approval to loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics SA) for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma. This marketing application was granted priority review and orphan drug designation by FDA. The review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

Loncastuximab tesirine (ADCT-042) is an antibody-drug conjugate composed of an anti-CD19 humanized IgG1k antibody conjugated via a linker to pyrrolobenzodiazepine-dimer toxin that induces the killing of CD19-expressing malignant B cells.

The BLA submission was supported by data from the open-label, single-arm Phase 2 LOTIS 2 study (NCT03589469), which evaluated the safety and efficacy of loncastuximab tesirine for the treatment of patients with relapsed or refractory DLBCL following ≥2 lines of prior systemic therapy. A total of 145 patients received loncastuximab tesirine as an intravenous infusion over 30 minutes on Day 1 of each cycle (every 3 weeks) at a dose of 150 μg/kg for 2 cycles, then 75 μg/kg for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria. The primary outcome measure is the overall response rate (ORR). Positive initial data from LOTIS 2 were presented during the virtual 25th Annual Congress of the European Hematology Association. The ORR was 48.3% (70/145 patients), the complete response rate was 24.1% (35/145 patients), and the median duration of response was 10.25 months. The toxicity profile was manageable and no new safety concerns were identified.

Need help keeping up to date on US and EU approvals?

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format.