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Two new antibody therapeutics enter FDA review

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The first biologics license applications (BLAs) for two antibody therapeutics, balstilimab (AGEN2034) and loncastuximab tesirine (ADCT-042), have recently been submitted to the US Food and Drug Administration, bringing the total number of antibody therapeutics undergoing a first review to 18 (see table here for details).

Balstilimab (Agenus Inc.)

Balstilimab (AGEN2034) is a human IgG4k antibody directed against PD-1, a negative regulator of immune activation expressed by T cells. Numerous antibodies that target PD-1 or its ligand PD-L1 (e.g., pembrolizumab, nivolumab, cemiplimab, avelumab, durvalumab) are marketed as treatments for solid tumors as well as lymphoma. Agenus’ clinical studies of balstilimab have focused on its use, either as monotherapy or in combination with anti-CTLA4 zalifrelimab (AGEN1884), as a treatment for cervical cancer.  FDA granted both balstilimab and the balstilimab/ zalifrelimab combination Fast Track designations for the treatment of cervical cancer. On September 18, 2020, Agenus Inc. announced that they had initiated a rolling BLA to FDA for balstilimab as monotherapy for the treatment of recurrent/metastatic cervical cancer. Agenus controls worldwide rights to balstilimab, except for certain South American rights, which are controlled by Recepta Biopharma, and Greater China rights, which are exclusively licensed to Betta Pharmaceuticals.

Data from a randomized, blinded, non-comparative, two-arm Phase 2 study (NCT03894215) supported the BLA submission. This study evaluated the efficacy and safety of balstilimab as monotherapy or in combination with zalifrelimab for treatment of patients with advanced cervical cancer who relapsed or progressed after receiving first-line platinum-based chemotherapy for a maximum of 24 months, or until disease progression or unacceptable toxicity. The goal of the study is to evaluate the efficacy of each arm against its relevant historical controls. The primary outcome measure is the objective response rate (ORR) to balstilimab administered with placebo (Treatment Arm 1 – monotherapy), or with zalifrelimab (Treatment Arm 2 – combination therapy). Data from the study were presented at the 2020 European Society for Medical Oncology Virtual Congress. Of 160 patients included in the balstilimab monotherapy arm, the ORRs in PD-L1-positive patients and all patients were 19% and 14%, respectively. Of 143 patients included in the balstilimab/ zalifrelimab combination arm, the ORRs in PD-L1-positive patients and all patients were 27% and 22%, respectively.

Loncastuximab tesirine (ADC Therapeutics SA)

Loncastuximab tesirine (ADCT-042) is an ADC composed of an anti-CD19 humanized IgG1k antibody conjugated via a linker to pyrrolobenzodiazepine (PBD)-dimer toxin that induces the killing of CD19-expressing malignant B cells. The FDA granted Orphan Drug designation to ADCT-402 for the treatment of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. On September 21, 2020, ADC Therapeutics SA announced the submission of a BLA to FDA for loncastuximab tesirine for the treatment of patients with relapsed or refractory DLBCL.

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 IV 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 (CRR) 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.

First study results for anti-SARS-CoV-2 antibody LY-CoV555

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On September 16, 2020, Eli Lilly and Company announced proof of concept data from an interim analysis of the Phase 2 BLAZE-1 clinical trial (NCT04427501) of LY-CoV555 (also known as LY3819253), an anti-SARS-CoV-2 IgG1 antibody. The randomized, double-blind, placebo-controlled study included 4 arms (placebo, 700 mg, 2800 mg, and 7000 mg administered intravenously (IV)), and enrolled mild-to-moderate recently diagnosed COVID-19 patients. Treatment is provided in an outpatient setting. The study was initiated on June 17, 2020 and has an estimated primary completion date of September 20, 2020.

  • The prespecified primary endpoint, change from baseline in viral load at day 11, was met at the 2800 mg dose level, but not the others. Additional analyses of viral data demonstrated that LY-CoV555 improved viral clearance at an earlier time point (day 3) and reduced the proportion of patients with persistently high viral load at later time points. Most patients, including those receiving placebo, demonstrated near complete viral clearance by day 11.
  • Analysis of pooled data from all dose groups indicated the rate of hospitalizations and ER visits was 1.7% (5/302) for LY-CoV555 vs. 6% (9/150) for placebo. Across all treatment groups (including placebo), no patients progressed to mechanical ventilation or died.
  • Viral RNA sequencing revealed putative LY-CoV555-resistance variants in placebo and all treatment arms. The rate of resistance variants was numerically higher in treated patients (8 percent) versus placebo (6 percent).
  • LY-CoV555 was well-tolerated, with no drug-related serious adverse events reported. Treatment emergent adverse events were similar across all dose groups and comparable to placebo.

Details for the BLAZE-1 study were updated on August 21, 2020 to include an experimental treatment arm comprising LY3819253 + LY3832479 (also known as LY-CoV016) administered IV.  LY-CoV016 binds a different epitope in the SARS-CoV-2 spike region compared to LY-CoV555. Across all treatment arms, the trial will enroll an estimated 800 participants.

Summary data for all anti-SARS-CoV-2 antibodies in clinical studies can be found here.

FDA issues Emergency Use Authorization for COVID-19 convalescent plasma

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On August 23, 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for investigational COVID-19 convalescent plasma (CCP) for the treatment of COVID-19 in hospitalized patients. CCP is human plasma collected by FDA-registered blood establishments from individuals whose plasma contains anti SARS-CoV-2 antibodies, and who meet all donor eligibility requirements and are qualified. Titer levels of anti-SARS-CoV-2 antibodies are determined by the Ortho VITROS SARS-CoV-2 IgG test before units of CCP are released. Units found to have a signal-to-cutoff ratio of 12 or greater qualify as High Titer COVID-19 Convalescent Plasma.

Based on scientific evidence available, the FDA concluded CCP may be effective in treating COVID-19, and that the known and potential benefits of CCP outweigh the known and potential risks of the product. The EUA authorizes the distribution of COVID-19 convalescent plasma in the U.S. and its administration by health care providers, as appropriate, to treat suspected or laboratory-confirmed COVID-19 in hospitalized patients with COVID-19.

Data obtained from the ongoing National Convalescent Plasma Expanded Access Protocol (EAP) sponsored by the Mayo Clinic was included in FDA assessment. This uncontrolled, single-arm study was established in April 2020 to provide access to COVID-19 convalescent plasma in hospitalized subjects with severe or life-threatening COVID-19 or judged by the treating provider to be at high risk of progression to severe or life-threatening disease. As of August 13, 2020, over 90,000 patients have been enrolled. Data from the EAP posted online on August 12, 2020 reveals trends toward reduced mortality when patients receive CCP with higher antibody levels and at earlier time points. According to FDA’s decision memorandum:

  • In the subset of non-intubated patients, there was a 21% reduction in 7-day mortality (from 14% to 11%, p=0.03) in subjects transfused with high versus low titer CCP.
  • In the subgroup of patients less than 80 years of age who were not intubated and who were within 72 hours of diagnosis, a significant reduction in 7-day mortality from 11.3 to 6.3% (p = 0.0008) was observed when titers are binned to low versus high.
  • Survival trends observed at 7 days persisted over a longer time period, with significantly improved survival in non-intubated patients (p=0.032) and a larger benefit in the subset of patients not intubated at the time of treatment, less than 80 years of age, who were treated within 72 hours of diagnosis (p=0.0081)

However, there was no difference in 7-day survival in the overall population between subjects transfused with high versus low titer CCP, and there was no apparent association between neutralizing antibody titers and 7-day mortality in intubated subjects.

Information from the EUA and clinical studies of CCP may inform the development of other biologic COVID-19 interventions, such as recombinant anti-SARS-CoV-2 antibodies.  The Antibody Society is currently tracking 10 such antibodies in clinical studies or with clinical studies pending. We will report on the progress of these molecules and other COVID-19 interventions in the future.

Satralizumab-mwge (ENSPRYNG) granted FDA approval

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On August 14, 2020, the US Food and Drug Administration approved satralizumab-mwge (ENSPRYNG) for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. NMOSD is a rare autoimmune disorder of the central nervous system that primarily damages the optic nerve(s) and spinal cord, causing blindness, muscle weakness and paralysis. ENSPRYNG was previously approved in Canada, Japan and Switzerland. Applications are under review with other regulatory agencies, including in the European Union and China.

ENSPRYNG is a recombinant humanized IgG2 antibody targeting interleukin-6 (IL-6) receptor. The efficacy of ENSPRYNG for the treatment of NMOSD in adult patients was established in two studies. SAkuraStar (NCT02073279) was a randomized (2:1), placebo-controlled trial in 95 patients without concurrent immunosuppressive therapy (IST) in which 64 patients were anti-AQP4 antibody positive and 31 patients were anti-AQP4 antibody negative. SAkuraSky (NCT02028884) was a randomized (1:1), placebo-controlled trial in 76 adult patients with concurrent IST. Of these, 52 adult patients were anti-AQP4 antibody positive and 24 adult patients were anti-AQP4 antibody negative. In the SAkuraStar monotherapy study’s AQP4 antibody positive subgroup, 76.5% of Enspryng-treated patients were relapse-free at 96 weeks, compared to 41.1% with placebo. In the SAkuraSky study, which evaluated Enspryng when used concurrently with baseline IST, 91.1% of Enspryng-treated AQP4 antibody positive subgroup patients were relapse-free at 96 weeks, compared to 56.8% with placebo. Based on results of the clinical studies, the recommended loading dosage of ENSPRYNG for the first three administrations is 120 mg by subcutaneous injection at Weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks.

Satralizumab-mwge is the 8th antibody therapeutic to be granted a first approval in the US or EU in 2020.

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. Information about other antibody therapeutics that may enter regulatory review in 2020 can be found in ‘Antibodies to watch in 2020’.

Emergency Use Authorization requested for leronlimab

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On August 12, 2020, Cytodyn requested that the Food and Drug Administration grant an Emergency Use Authorization for leronlimab for mild to moderate COVID-19 based on data from the Phase 2 CD10 study (NCT04343651). In this study, patients were randomized to receive weekly doses of 700 mg leronlimab or placebo, both of which were administered via subcutaneous injection. Top-level results of the study showed that, in patients with Total Clinical Symptom Scores of ≥ 4 at baseline (higher scores equate to poorer health state), at Day 3, more subjects treated with leronlimab reported improvement in total clinical symptom score compared to the placebo group (90% on leronlimab arm vs. 71% on placebo). The EUA request was disclosed in an investment community conference call that will be available until September 12, 2020.

  • Leronlimab is a humanized IgG4 antibody targeting C-C chemokine receptor type 5.