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ADVERTISEMENT FEATURE New mechanism of action for treatment
of autoimmune diseases
TheraMAB is progressing clinical development of its new regulatory T cell activator for use in rheumatoid
arthritis and other autoimmune disorders on the strength of encouraging results in recent phase 1 trials.
TheraMAB is an emerging biopharma- Progressing the science
by slow infusion over 4–12 hours. Volunteers ceutical company that is developing a The well-known first-in-human trial that began in received close clinical surveillance for 48 hours new approach to treating autoimmune London in March 2006 ended abruptly when six followed by repeated clinical tests for 8 weeks.
diseases that aims to control autoimmunity healthy volunteers experienced a life-threatening None of the 30 volunteers enrolled presented without causing general immunosuppression. cytokine release syndrome that had not been a cytokine release syndrome during the study, Existing treatments act in various ways to predicted by preclinical testing2. Subsequent which was completed in 20131. Assessment suppress or block the immune system, which research has revealed several limitations of the of the cytokine response showed that the key carries the risk of side effects such as infec- in vitro assays and animal models that were used cytokine release syndrome –promoting cyto- tions and lymphoma, whereas a conceptually to calculate a starting dose of antibody, which kines: tumor necrosis factor, interferon-γ and different approach could offer more efficient resulted in a dramatic overdose of the drug3.
interleukin-2, remained at baseline levels over and safer drugs.
TheraMAB has heeded the lessons and has the full range of doses and observation time. Regulatory T cells (T cells) are known to play brought TAB08 back into clinical development The drug was well tolerated with no dose-limit- a key role in the pathogenesis of autoimmune based on new evidence from different preclini- ing adverse events observed. Notably, the key inflammatory conditions such as rheumatoid cal studies. A pivotal factor was the invention of anti-inflammatory T cell signature cytokine arthritis, systemic lupus erythematosus a new in vitro cell-based assay called RESTORE interleukin-10 was detected in the plasma of (SLE), psoriasis and multiple sclerosis, which (RESetting T cells to Original REactivity), which the cohorts that received the highest doses of are associated with defects in the number or improves the reactivity of circulating T cells to sol- study drug (5 μg/kg and 7 μg/kg, which were function of T cells.
uble stimulants. The RESTORE protocol involves 15–20 times lower than the dose used in the A new type of monoclonal antibody specific for two days of preculture at a tenfold-higher cell 2006 trial), indicating that TAB08 had stimu- the cell-surface transmembrane glycoprotein density than is usually used for standard in vitro lated an anti-inflammatory response.
CD28, which is expressed on T lymphocytes, has assays and thus mimics tissue-like conditions "Our positive results to date are due to a com- been shown to preferentially activate T cells in and restores T cell responsiveness to TAB084.
bination of serious scientific analysis, a novel, rodents and in vitro in humans. The patented RESTORE assay has been used thoroughly designed preclinical program and a This CD28 superagonist is also highly to re-examine the in vitro activity of TAB08 in a careful, stepwise clinical strategy of the evalu- efficacious in numerous preclinical models of series of experiments using blood cells from both ation of safety parameters," said Dmitry Tyrsin, autoimmunity, inflammation, transplantation and healthy volunteers and patients with rheumatoid CEO of TheraMAB.
tissue repair1.
arthritis1. The results confirmed that TAB08 "The key advantage over existing blocking administration at low doses does not trigger cyto- Clinical trial program therapies, like infliximab, is that you do not need kine release and leads to preferential expansion Following this successful clinical study, a phase to continuously load the body with high levels and activation of T cells.
1b trial was started in 2013 to assess the safety, of a blocking antibody," said Thomas Hünig, tolerability, pharmacodynamics and efficacy of a professor at the Institute for Virology and Individualized approach multiple TAB08 doses in patients with moderate- Immunobiology at the University of Würzburg, an The RESTORE assay has the potential to fill the to-severe active rheumatoid arthritis who had an inventor and a scientific adviser for TheraMAB. gap between in vitro testing and animal models inadequate response to methotrexate at a dose "Instead, by applying much lower doses of prior to first-in-human trials as it enables per- ≥10 mg/week. The open-label trial has enrolled CD28 superagonist, you transiently kick off a sonalized testing of immunogenicity, toxicity 9 patients who were divided into 3 cohorts to test wave of T cell activation, and these cells then and response to new immunomodulatory drug 3 different doses of TAB08: 5, 7 and 10 μg/kg swarm through the body and seek out the site candidates; this can be especially important if of body weight. The study regimen of four intra- of inflammation, where they remain to do their an animal model is not available or is ethically venous infusions of TAB08 at the assigned dose job while the rest of the system goes back to unacceptable. TheraMAB has already trialed was given once weekly for four weeks. Infusion normal." (Fig. 1.) this approach successfully as part of the safety time was decreased gradually over the study TheraMAB was incorporated in 2009 by the precautions for its open-label phase 1a study, period from a maximum of eight hours for the first Moscow-based investment fund Bioprocess which assessed the pharmacokinetics and toler- dose to a minimum of one hour for the final dose.
Capital Ventures and the German biotechnology ability of a single intravenous infusion of TAB08 in Results to date support the good tolerability of company TheraMAB GmbH. The company healthy adult volunteers. Each volunteer was pre- TAB08 that was observed in the phase 1a trial. has resumed clinical development of the screened with the RESTORE assay to determine No serious adverse events occurred and no dose- CD28 superagonist TGN1412 under the new individual sensitivity of blood cells to stimulation limiting toxicities were detected during the study.
name TAB08 (theralizumab). TheraMAB has Although efficacy assessment was not the demonstrated that TAB08 can be administered The phase 1a study tested 9 ascending doses primary objective of the study, all participants safely to both healthy volunteers and patients of TAB08, from 0.1 μg per kg of body weight up to experienced some beneficial treatment effects, with rheumatoid arthritis, and preliminary phase 7 μg/kg, with escalation of each dose of TAB08 with some patients experiencing marked improve- 1b findings show promising efficacy results.
approved by an independent drug safety expert ments in rheumatoid arthritis symptoms at TheraMAB is now seeking further investment council after careful analysis of interim safety eight weeks after the final infusion of TAB08. to help it complete the next stages of clinical reports. The healthy volunteers were given ade- Assessments using the American College of development of this first-in-class, humanized quate premedication, including antihistamines Rheumatology (ACR) response criteria at the monoclonal antibody of the IgG4 subclass.
and paracetamol, and TAB08 was administered 8-week follow-up showed that ACR 20 responses ADVERTISER RETAINS SOLE RESPONSIBILITY FOR CONTENT ADVERTISEMENT FEATURE "The results obtained are very encouraging. TAB08 has the potential to meet the substantial medical need of patients suffering from rheuma-toid arthritis and other autoimmune diseases." TheraMAB is now seeking a partner to help support the ongoing clinical development of TAB08. The next step will be a randomized, double-blind phase 2a study, which is expected to begin in the first quarter of 2015. Up to 150 patients with rheumatoid arthritis will be randomized to 1 of 3 arms to compare the effects of 2 different doses of TAB08 with placebo. The treatment regimen will be given in combination with methotrexate and will involve a four-week cell-loading therapy of weekly intravenous infusions followed by support therapy of monthly intravenous infusions for four months. Assessments will include dose-limiting toxicity and adverse events as well as pharmacokinetics, immunogenicity, ACR 20/50/70 response rates, European League Against Rheumatism (EULAR) response criteria and patient-reported outcomes. In addition, Figure 1. The new mechanism of action of CD28 superagonists means that they require much new preclinical studies of subcutaneous use lower doses than anti–tumor necrosis factor antibodies to treat rheumatoid arthritis. Infliximab of TAB08 have been initiated, and there are neutralizes tumor necrosis factor (TNF) both locally and systemically (left) and needs to be supplied plans to develop a new formulation of TAB08 at high doses in order to block TNF at the site of inflammation. In contrast, the CD28 superagonist for subcutaneous administration.
TAB08 (theralizumab) is effective at low doses (at least 100-fold less than doses of cytokine- The mechanism of action and good preclinical neutralizing antibodies) because it activates regulatory T cells (T cells) in tissues, which migrate data suggest that TAB08 may also be effective for to the inflamed joint (right). treating other autoimmune diseases such as SLE and psoriasis, which are characterized by acute (decrease of disease activity by at least 20%) and chronic inflammation of various tissues of were observed in 5 of the 9 patients treated with the body. The available therapies for SLE have TAB08. In addition, 2 patients had improvements limited efficacy and are often associated with in response criteria of 50% (ACR 50), whereas severe side effects. TheraMAB plans to submit 1 patient achieved complete remission (mark- a clinical study protocol to the regulatory bodies edly over ACR 70), which has been sustained in the first quarter of 2015 for a phase 2 study in for longer than 4 months. Importantly, improve- patients with SLE.
ments in some ACR parameters were already Hünig believes the potential for TAB08 is even observed after the first infusion of TAB08, and broader. "There are more than 20 published those changes became more pronounced after preclinical models showing the benefits of using "The presentation of our four weeks of the therapy.
CD28 superagonists for a wide range of autoim- phase 1a/1b results at
Individual components of the ACR score, tender mune diseases," he said. "Basically, everywhere joint count and swollen joint count, were also ana- the T cells do their job, one can apply this recent meetings has drawn lyzed. An improvement of at least 20% for both approach of transient T cell activation. Thus,
tender and swollen joint count was reported in 8 TAB08 has the potential to meet the significant significant interest from
of the 9 patients at the end of 4 weeks of treat- medical needs of patients suffering from various ment. In addition, an improvement of at least autoimmune disorders." both scientists and
50% was reported in 5 patients, while 2 patients reported at least 70% improvement.
An additional analysis of pharmacodynamic 1. Tabares, P. et al. Eur. J. Immunol. 44, 1225–1236 (2014). data from the phase 1b trial indicated that lon- 2. Suntharalingam, G. et al. N. Engl. J. Med. 355, 1018–1028 ger administration of TAB08 could provide higher efficacy and that the drug could be administered 3. Hünig, T. Nat. Rev. Immunol. 12, 317–318 (2012).
less frequently (every other week or monthly 4. Römer, P.S. et al. Blood 118, 6772–6782 (2011). infusions) for longer periods. Overall, the results support a favorable risk-to-benefit ratio for TAB08 use in patients with rheumatoid arthritis and jus-tify further clinical studies.
"The presentation of our phase 1a/1b results Dmitry Tyrsin, CEO at recent meetings has drawn significant interest from both scientists and clinicians," said Tyrsin. ADVERTISER RETAINS SOLE RESPONSIBILITY FOR CONTENT

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