Trubion Pharmaceuticals, Inc, (SEATTLE, Wash.), a biopharmaceutical company focused on developing treatments for autoimmune diseases and cancer, announced it has initiated a phase IIb clinical trial of TRU-015, the company's lead Small Modular ImmunoPharmaceutical (SMIPâ„¢) CD20-targeted drug candidate for the treatment of rheumatoid arthritis (RA) via B-cell depletion. The phase IIb randomized, double-blind, placebo-controlled clinical trial will enroll approximately 280 RA patients and is designed to evaluate clinical response rates in patients with RA. These patients will be randomized into five groups to evaluate the safety and efficacy of an infused dose of TRU-015, ranging from 200 mg to 1600 mg per patient, compared to placebo for a 24-week period.
With initiation of this phase IIb study and pursuant to the terms of its strategic alliance with Wyeth Pharmaceuticals for the discovery, development, and commercialization of SMIP-based CD20-targeted therapies for RA, as well as other chronic inflammatory and B-cell mediated diseases, Trubion will receive an aggregate of $8 million as a milestone payment and reimbursement of prior manufacturing-related costs associated with TRU-015. As part of the initial transaction, Trubion received a $40 million payment, and if all milestones are achieved the total payments to Trubion could exceed $800 million, excluding royalties and co-promotion fees.

SMIPs are single-chain polypeptides that are engineered for the full binding and activity function of a monoclonal antibody.  Approximately one-third to one-half the size of conventional therapeutic monoclonal antibodies, SMIP drugs can reach tissue sites inaccessible to larger molecules. In addition, SMIP drugs exhibit selective target binding and long in vivo half-lives. SMIP drugs contain three distinct modular domains: a binding domain, a hinge domain, and an effector domain. Trubion incorporates key design modifications into each domain. The binding domain may consist of any protein that confers specificity. The hinge domain performs two complementary functions by providing a flexible link between the binding domain and effector domain while also controlling multimerization of the SMIP drugs. The effector domain determines which type of immune cell is activated and regulates the balance of effector functions employed, including the relative activity of antibody dependent cellular cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC).

Effector domains also can be engineered to regulate SMIP drug multimerization. Trubion selects specific effector domains based on the molecular target and desired clinical indication.

TRU-015 is designed to target and deplete B-cells using a balance of effector functions optimized for autoimmune and inflammatory diseases. TRU-015 binds to its target, CD20, and is engineered for potent ADCC activity and attenuated CDC activity. In vitro and in vivo studies on TRU-015 demonstrate B-cell CD20 binding, ADCC and apoptosis activity, and reduced CDC activity compared to rituximab (RituxanR, a CD20-targeted monoclonal antibody). Studies in RA patients treated with rituximab suggest that B-cell depletion results in significant clinical improvement. There is evidence to suggest CDC may be associated with rituximab side effects, especially infusion reactions. In addition, general systemic complement activation is thought to initiate or exacerbate symptoms in RA patients. TRU-015 has been demonstrated to effectively deplete B-lymphocytes in cynomolgus monkeys in a dose-dependent manner and to improve survival in mouse xenograft tumor models.

A phase I study included 37 RA patients on background methotrexate who were enrolled into one of eight dosage groups with each subject receiving TRU-015 as an intravenous infusion. Patients received either a single dose of TRU-015 at either 0.015 mg/kg, 0.05 mg/kg, 0.15 mg/kg, 0.5 mg/kg, 1.5 mg/kg, 5 mg/kg or 15 mg/kg. The last cohort received a total dose of 30 mg/kg of TRU-015 as two 15 mg/kg infusions administered 1 week apart. At least four patients were exposed at each dose level. TRU-015 was generally well tolerated; no dose-limiting toxicities were observed, and no serious adverse events were reported. Decreases in peripheral B-cell counts were observed in all dose groups at the first time-point after drug administration (24 hr), with doses >0.5 mg/kg causing depletion of peripheral B-cells. The degree, duration, and recovery of B-cell depletion were dose dependent. Pharmacokinetic parameters of TRU-015 were calculated for cohorts receiving 0.5 mg/kg and higher. The overall mean half-life of TRU-015 was 295 hours.

In the first 24 weeks after RA patients received intravenous infusions of TRU-015 in a phase IIa study designed to demonstrate proof of concept that TRU-015 measurably improves the signs and symptoms of RA, 72% of the subjects experienced a clinical response that is equal to or greater than that required to achieve an ACR20 response, 28% achieved an ACR50 response and 12% achieved an ACR70 response.

Trubion is planning to issue four million shares for $13 to $15 per share in an initial public offering. The underwriters (Morgan Stanley, Banc of America Securities LLC, Pacific Growth Equities, LLC, and Lazard Capital Markets) will have the option to buy an additional 600,000 shares in the event of high demand.

—A. Techman

The Rheumatologic Perspective

TRU-015 is another attempt to engineer small polypeptides into designer molecules that have all the advantages of antibodies but have been designed to include specific desired properties and avoid unwanted characteristics. This particular reagent targets B cells by binding the B cell specific molecule, CD20, and includes an effector domain that engages ADCC. As such, it is designed to specifically delete B cells. It is postulated that this molecule may be as effective as rituximab, a chimeric monoclonal antibody that has recently been approved for patients with rheumatoid arthritis who have failed anti-TNF therapy. Except for data from a small phase I trial, there is little information about TRU-015 in the public domain, and therefore, there are a number of unanswered questions. First, will the small size of the reagent make it more effective than rituximab because it might be able to penetrate into regions that cannot be accessed by the larger monoclonal antibody? Is so, will this increase effectiveness or possibly toxicity? Secondly the reagent has been engineered to avoid complement mediated cytotoxicity. However, there is evidence that some B cell populations are deleted by rituximab via complement mediated toxicity. This raises the question of whether TRU-015 will be as effective as rituximab., Thirdly TRU-015 is a completely novel construct that may be seen as foreign by the human immune system. Is there evidence for the development of an immune response to this reagent and might that be associated with decreased effectiveness or increased toxicity?, Finally, because of its small molecular weight, will it be easier and cheaper to manufacture and will it therefore be less expensive to patients? The results of the ongoing clinical trials might provide answers to these and other questions that will be important in determining whether TRU-015 will emerge as a pharmaceutical candidate and whether this category of "designer" molecules will become viable alternatives to monoclonal antibodies as targeted therapies.

 

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