The Antibody Society

the official website of the antibody society

An international non-profit supporting antibody-related research and development.

FDA issues a complete response letter for teplizumab BLA

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Provention Bio, Inc. has announced that the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter relating to the company’s biologics license application (BLA) for teplizumab for the delay of clinical type 1 diabetes (T1D) in at-risk individuals. In the letter, the FDA stated that a single, low-dose pharmacokinetic/pharmacodynamic (PK/PD) bridging study in healthy volunteers to compare planned commercial product with drug product originating from drug substance manufactured for historic clinical trials had failed to show PK comparability. This deficiency, and others noted in the letter, will need to be suitably addressed before approval.

Teplizumab (PRV-031) is a humanized IgG1k that binds to an epitope of the CD3-epsilon chain expressed on mature T lymphocytes, and thereby modulates the pathological immunologic responses underlying T1D and other autoimmune diseases. Teplizumab was granted FDA’s Breakthrough Therapy designation for the prevention or delay of clinical T1D, and EMA granted teplizumab PRIME designation for the prevention or delay of clinical T1D in individuals at risk of developing the disease. Provention Bio acquired worldwide development and commercialization rights to teplizumab from MacroGenics, Inc. in 2018.

A rolling BLA for teplizumab for the delay or prevention of clinical Type 1 Diabetes (T1D) in at-risk individuals, as indicated by the presence of two or more T1D-related autoantibodies, was started in April 2020 and completed by November 2020. The BLA includes data from the Phase 2 “At-Risk” study (NCT01030861), which evaluated whether administration of teplizumab can prevent or delay the development of T1D in high-risk autoantibody-positive non-diabetic relatives of patients with T1D.  Participants received IV infusions of teplizumab given for 14 consecutive days (n=44) or placebo (n=32). Extended follow-up data showed that, compared to placebo, one course of teplizumab delayed insulin-dependence in presymptomatic T1D patients by a median of approximately three years. Participants in the “At-Risk” study who develop clinical type 1 diabetes after the conclusion of that trial can enroll in an extension study (NCT04270942) and receive teplizumab treatment within one year of diagnosis of clinical type 1 diabetes.

Teplizumab is also being evaluated in the Phase 3 PROTECT study (NCT03875729), which will determine whether teplizumab slows the loss of β cells and preserves β cell function in children and adolescents 8-17 years old who have been diagnosed with T1D in the previous 6 weeks. Estimated enrollment for the PROTECT study is 300 patients, and the estimated primary completion date is May 2022.

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 in the Web Resources section of our website.

Actemra® (tocilizumab) granted emergency use authorization for the treatment of COVID-19

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On June 24, 2021, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for intravenous Actemra® (tocilizumab) for the treatment of COVID-19 in hospitalized adults and pediatric patients (2 years of age and older) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation. The EUA was issued to Genentech Inc.

Actemra is a recombinant humanized monoclonal antibody that inhibits inflammation by selectively binding to both soluble and membrane-bound human IL-6 receptors and subsequently inhibiting IL6-mediated signaling through these receptors. The data supporting Actemra’s EUA are derived from four clinical trials, the randomized, controlled, open-label, platform trial “Randomised Evaluation of COVID-19 Therapy” (RECOVERY) and three randomized, double-blind, placebo-controlled trials (EMPACTA, COVACTA and REMDACTA). The most important scientific evidence on the potential benefit of Actemra for its authorized use came from the RECOVERY and EMPACTA trials.

The EUA for Actemra is not equivalent to an approval. According to current labeling, Actemra is FDA approved for rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome.

Tralokinumab granted first approval in the European Union

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The European Commission has approved Adtralza® (tralokinumab) for the treatment of moderate-to-severe atopic dermatitis in adult patients who are candidates for systemic therapy. The European Commission decision is valid in all European Union Member States, Iceland, Norway, and Liechtenstein.

Tralokinumab is a human IgG4l antibody targeting IL-13, a pleiotropic T helper type 2 cytokine associated with atopic dermatitis and other inflammatory disorders. The antibody interferes with IL-13-mediated signaling by blocking its interactions with both IL-13 receptor α1 and IL-13 receptor α2. Originally identified by Cambridge Antibody Technology and developed by MedImmune as CAT-354, AstraZeneca sold the rights to tralokinumab in dermatology indications to LEO Pharma in 2016.

The marketing applications are supported by data from three Phase 3 studies, ECZTRA 1 (NCT03131648), 2 (NCT03160885), and ECZTRA 3 (NCT03363854). The randomized, double-blind, placebo-controlled, multinational, 52-week ECZTRA 1 and ECZTRA 2 trials evaluated the safety and efficacy of tralokinumab (300 mg SC) as monotherapy in adults with moderate-to-severe atopic dermatitis who were candidates for systemic therapy. ECZTRA 3 was a double-blind, randomized, placebo-controlled, multinational 32-week study of 380 patients that evaluated the safety and efficacy of tralokinumab (300 mg SC) in combination with topical corticosteroid in adults with moderate-to-severe atopic dermatitis who were candidates for systemic therapy.

The results of the three Phase 3 studies were recently published in the British Journal of Dermatology. [1] The primary outcome measures for the studies included an Investigator’s Global Assessment (IGA) of 0 or 1 and 75% improvement in Eczema Area and Severity Index (EASI 75) at Week 16. At this time point in the ECZTRA 1 and ECZTRA 2 studies, 15.8% and 22.2% of patients who received tralokinumab achieved an IGA score of 0/1 vs. 7.1% and 10.9% of patients who received placebo, respectively. More patients who received tralokinumab also achieved EASI 75 compared to those who received placebo (25.0% vs. 12.7% and 33.2% vs. 11.4% in ECZTRA 1 and ECZTRA 2, respectively). In the ECZTRA 3 study, which included use of topical corticosteroid, 38.9% patients who received tralokinumab achieved IGA 0/1 vs. 26.2% of those who received placebo. EASI 75 was achieved in 56.0% patients who received tralokinumab vs. 35.7% of those who received placebo. [2]

1. Wollenberg A, Blauvelt A, Guttman-Yassky E, Worm M, Lynde C, Lacour JP, Spelman L, Katoh N, Saeki H, Poulin Y, et al. Tralokinumab for moderate‐to‐severe atopic dermatitis: results from two 52‐week, randomized, double‐blind, multicentre, placebo‐controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2020. doi: 10.1111/bjd.19574.

2. Silverberg JI, Toth D, Bieber T, Alexis AF, Elewski BE, Pink AE, Hijnen D, Jensen TN, Bang B, Olsen CK, Kurbasic A, Weidinger S. Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial. Br J Dermatol. 2020. doi: 10.1111/bjd.19573.

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.

Funding the Development of Antibody Innovations: Part 4: Exit Strategies for Investors in Antibodies

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By Tom Burt (Partner, Sofinnova Partners) & Nick Hutchinson (BSG Lead, Mammalian Cell Culture, FUJIFILM Diosynth Biotechnologies)

Start-up antibody companies need substantial amounts of capital to fund the late-stage clinical development of lead candidates and grow their clinical pipelines. In our 3rd post, we described the role of Venture Capitalists (VCs) in funding the early-phase development of antibody therapeutics and introduced the concept of crossover investors (1). In this, our final post in the series, we look at the final stage of the financing cycle and describe how early investors may seek to exit with a return on their investment.

According to Tom Burt of Sofinnova Partners, the emergence of crossover investors in the past 5 years has accelerated the path to the public markets for many ‘early-stage’ biotech companies. “Crossover investors’ have flexible criteria around the clinical stage of the company’s lead program that has led to their participation in earlier private rounds such as Series A/ B funding. Furthermore, it has resulted to the counter-intuitive situation where, on average, preclinical companies can command higher pre-IPO valuations than their later-stage peers (2; Figure). In these cases, it is because the crossover candidates encompass highly differentiated or novel modalities, including antibody-drug conjugates,  bispecific and multi-specific antibodies,” he says.

According to Tom, a start-up can continue to raise capital from the private markets in later-stage financings such as Series C and onwards despite the absence of a crossover financing round. “It may choose to do this for the following reasons: 1) crossover investors don’t believe the company can command the minimally accepted IPO valuation required to go public in the US of over c.$300m; 2) existing investors may believe they can command a higher IPO valuation if they wait, pursue an additional financing round and reach a milestone event such as a clinical trial readout, or 3) existing investors feel there is a high chance the company may strike a value-driving partnership or be acquired in the near-term,” he says.

EpimAb’s three rounds of funding

EpimAb is one such company that progressed to Series C funding. It is a start-up antibody company that initially raised $25 million in a Series A round and put it to use to develop its proprietary Fabs-In-Tandem Immunoglobulin technology platform. The platform generates antibody-like bispecific molecules designed to be more potent, less immunogenic and easier to manufacture than those produced by other bispecific antibody technologies. It was able to build a pipeline of candidates and progress the first into clinical trials with the cash (3). In 2019, the company raised $74 million in Series B to build out the pipeline further, but also to progress its lead candidate, EMB-01 (targeting EGFR- and cMET) into Phase 2 clinical trials for oncology indications (4).

This year the company announced it had raised $120 million in Series C funding to further progress the clinical development of EMB-01, but also to fund the clinical trials for two other candidates. EMB-02 targets checkpoint proteins PD-1 and LAG-3, while EMB-06 is a T-cell-engaging bispecific that targets CD3 and BCMA. The company sees the three programs as pilot projects in three major areas of bispecific antibody development, namely, targeted oncology, dual checkpoint inhibition and T-cell engagement. It has licensed its technology to other companies which has provided income and helped validate the company ahead of a final round of private investment and subsequent IPO (5).

Tom says, “Generally, for investors in companies that pursue later private financings, an acquisition is always a preferable exit route over IPO. By this point, Series A investors may have been shareholders in the company for over five years and an acquisition represents a complete exit. If they attempt to exit through an IPO, they are restricted on selling down their shares immediately as these are locked up for at least 6 months following IPO, and even then can only be sold in a co-ordinated way that will not impact the share price.”

He continues “Assuming that EpimAb is not acquired before its current capital is exhausted, it may decide to pursue an IPO. The main attractions of an IPO are that: 1) public capital markets are much larger than private markets and can provide greater quantums of capital needed to pursue late-stage clinical development; and 2) it provides an exit route of sorts for earlier investors.“

Over the past few years NASDAQ has become the venue of choice for global biotech companies seeking to IPO. This is not to disparage European exchanges such as AiM or LSE, but generally the US market has much deeper pools of capital, comprising many more specialist public buyside investors who focus on public biotech stocks. Arguably, it makes little difference to the company where its shares are listed, since R&D operations can largely continue as before. Beyond this continuity though, the move to public status represents a step-change in how the company is owned, managed and regulated that is significantly different to its prior existence as a private company.

Conclusions

Innovations derived from the discovery and development of antibodies, especially therapeutic antibodies, come from scientists with creative minds, but large amounts of capital are needed to bring ideas to fruition. Many scientists will forge careers in companies that are not yet generating revenues, but are being funded by investors. Some scientists may opt to move out of research and work in the sector supplying inventors with the advice and funding required to progress their innovations. These opportunities include those in technology transfer, consultancies, analysts, and, of course, VCs themselves.

Ultimately, discoveries in antibody research and development will not benefit society, including patients suffering from serious diseases, unless scientists with passion take the bold step to commercialize their ideas by launching their own business and raising money to continue their development. The Antibody Society comprises a community with members that have done just that. Furthermore, our community has a huge amount of expertise that can help budding entrepreneurs with support ranging from mentoring, intellectual property advice through to recruiting management teams. We hope that this series of posts will kick-start introductions and discussions among Society members that will help establish the next generation of antibody companies.

(1)    Burt T. & Hutchinson N. (2021). Funding the Development of Antibody Innovations. Part 3: Crossover Investors. 
(2)    Cowen Healthcare (2021) Life Science Market Update March 2021.
(3)    GEN (2017) EpimAb Raises $25M in Series A to Progress Bispecific Antibodies into Phase 1. Genetic Engineering News. April 25, 2017.
(4)    Al Idrus, A. EpimAb bags $74M to push EGFR/cMET bispecific, build out pipeline. Fierce Biotech. June 5, 2019.
(5)    Al Idrus, A. (2021) EpimAb reels in $120M to propel 3 clinical-stage bispecifics, including dual checkpoint inhibitor. Fierce Biotech. March 22, 2021.

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.