Date: Thu, 18 Dec 1997 18:01:32 GMT Server: NCSA/1.5.2 Last-modified: Fri, 05 Dec 1997 15:34:06 GMT Content-type: text/html Content-length: 15272 Complement Inhibitors

Complement Inhibitors


T Cell Sciences is developing a new class of therapeutics based on inhibition of the complement system, a key triggering mechanism for the human inflammatory response. Medical problems that result from excessive complement activation affect millions of people throughout the world and represent multi-billion dollar market opportunities. They include:

The Company’s first product candidate, TP10, is now being evaluated in two separate efficacy trials - a Phase IIa trial for ARDS and a Phase I/II trial of reperfusion injury following lung transplants.

 

What is the Complement System?

The complement system consists of a series of blood proteins that when activated, undergo a cascading series of enzymatic interactions that ultimately trigger the human inflammatory response. This complement cascade is similar in mechanisms and importance to the blood enzyme cascades that make up the coagulation, fibrinolytic, and renin/angiotensin/kinin systems. Understanding the latter three major cascades has produced a number of important and life saving therapeutic products which inhibit or enhance each of these enzyme systems. For example, tissue plasminogen activator (t-PA) is an enzyme from the fibrinolytic cascade used to dissolve blood clots. Anti-coagulants, such as heparin, inhibit the coagulation cascade. ACE (angiotensin converting enzyme) inhibitors reduce hypertension (high blood pressure) caused by the renin/angiotensin/kinin system. To date, no therapeutic products are available to regulate the complement system. TP10, now undergoing human clinical testing, is the lead compound in this new class of therapeutics.

 

Cascade System

Drug Products

  • Coagulation
warfarin
heparin
  • Fibrinolytic
t-PA
streptokinase
  • Renin/Angiotensin/Kinin
ACE inhibitors
  • Complement
none

 

The complement system’s role is to defend the body rapidly and aggressively from infection or injury. It can be activated through infection by microorganisms such as bacteria, by direct cell injury, or during an immune response. When activated, the first protein in the system splits, creating an enzyme that then activates the next protein and so on, in a sequential fashion. The resulting enzyme cascade drives the inflammatory response that is necessary to protect the body. However, this response may also be destructive if inappropriately or chronically activated.

Activation of the complement cascade causes many down-stream inflammatory events: e.g., increased permeability of blood vessels; the activation and attraction of neutrophils; and the formation of the complement membrane attack complex which injures and kills tissue directly. In ARDS, complement activation causes increased blood vessel permeability of the lungs that results in fluid and blood cell leakage into that organ. During a heart attack, complement activation during the time of reperfusion kills the already injured tissue, significantly increasing the amount of damage to the heart.

 

Acute Complement-mediated Conditions


ARDS
Reperfusion Injury
Hyperacute Allograft Rejection
Xenograft Rejection

U.S. Population
250,000
1,100,000
30,000
n/a

Chronic Complement-mediated Conditions

Glomerulonephritis
Systemic Lupus Erythematosus
Rheumatoid Arthritis
Alzheimer’s Disease
Multiple Sclerosis

300,000
140,000
2,100,000
4,000,000
250,000

 

The economic opportunity available to a successful complement inhibitor is enormous. The company estimates the market potential for complement inhibitors in the range of $2 to 4 billion, an amount similar to the markets realized by drugs for other cascade systems.

 

Soluble Complement Receptor One

TP10 is the soluble form of a naturally occurring complement regulatory protein, complement receptor-1, or sCR1. This compound works at several points in the complement cascade to minimize all forms of complement-mediated inflammation. T Cell Sciences and its collaborators have evaluated TP10 in numerous preclinical animal models, resulting in over 60 peer reviewed publications since 1990. Today, approximately 50 academic research collaborations relating to TP10 are in progress.

In studies reported in Science, TP10 reduced the area of heart tissue damaged by 44 percent in a rat model of heart attack. Additional encouraging data have since been published supporting the protective effects of TP10 in limiting reperfusion injury in other models. Studies published in the Journal of Immunology show that TP10 significantly reduced complement-mediated lung permeability in four different animal models. In these models, TP10 also produced significant decreases in blood vessel leakage. Since complement plays a major role in recognizing and eliminating foreign (non-self) substances in the body, blocking unwanted complement activation may prove important in organ transplantation by preventing hyperacute (extremely rapid) rejection of allografts (same species transplants) and xenografts (cross species transplants). In animal models of hyperacute and acute (near term) rejection, published in Transplantation and Transplantation Proceedings, TP10 was shown to prolong significantly the survival of the transplanted organs in both allograft and xenograft models. Since the demand for organ transplants is greater than the supply of human donor organs, xenotransplantation may become a realistic alternative to allograft transplantation if hyperacute rejection can be prevented.

 

Clinical Development

Under the company’s direction, researchers completed the first phase I clinical trial of TP10 in patients at risk for ARDS in 1995. ARDS affects over 250,000 patients per year in the United States. Results of this trial were presented in October 1995 at the American College of Chest Physicians meeting. A second phase I safety trial for reperfusion injury was completed in December 1995 in patients with first-time myocardial infarction, which affects approximately 1.5 million Americans per year. This study was presented at the American Heart Association’s Joint Conference on Thrombosis, Arteriosclerosis and Vascular Biology in February 1996. In each of these trials, TP10 demonstrated excellent safety and pharmacokinetic profiles with no drug-related adverse events. In addition, the drug exhibited a clearance time of at least 70 hours and was able to inhibit complement activity in a dose-dependent manner.

With safety confirmed in two indications, efficacy testing of TP10 began in 1996 - the first complement inhibitor of any kind to advance to this level of testing in humans. In January 1996, a Phase IIa clinical trial of TP10 began in patients ARDS. In August 1996, enrollment began in a Phase I/II trial of TP10 in patients with reperfusion injury following lung transplantation. Patient accrual for this trial was completed in May 1997.

In October, T Cell announced positive results from the efficacy portion of our Phase I/II clinical study of TP10 in patients undergoing lung transplantation. The 60 patient trial was aimed at evaluating the ability of TP10 to reduce reperfusion injury (the vascular damage that often occurs following surgery or a heart attack, where a patient’s blood supply is shut off and then reintroduced) and improve lung function in patients with end-stage pulmonary disease who were undergoing lung transplant surgery. The results showed that 24 hours after surgery significantly fewer of the patients receiving TP10 required ventilation as compared to those receiving placebo. Moreover, those patients who received TP10 and also underwent cardiopulmonary bypass as part of the transplantation procedure showed significantly decreased intubation time and time on ventilation. Reduction in the time that a patient requires intubation and mechanical ventilation typically translates to better clinical outcome and also implies an economic benefit from reduced time in the ICU.

These findings in the area of reperfusion in a transplantation setting additionally support positive observations made previously in a Phase I study of TP10’s ability to prevent reperfusion injury in patients undergoing heart attacks. As a result, we plan to conduct further studies of this drug candidate in a cardiac reperfusion setting.

 

Complement Inhibitor Pipeline

In addition to TP10, T Cell has identified other product candidates to inhibit activation of the complement system. The lead candidate in preclinical development is an altered form of sCR1 (TP10) which the company has modified to add sLex carbohydrate structures. sLex is a sugar structure that mediates binding of certain white blood cells (neutrophils) to selectin proteins appearing on the surface of activated endothelial cells and platelets at the onset of inflammation. Selectin-mediated binding of circulating neutrophils to activated endothelial cells is a critical event in inflammation. Compared to TP10, the combined sCR1-sLex molecule has demonstrated increased functional benefits in in vitro and early in vivo experiments, and may be particularly useful in the treatment of heart attacks and stroke.

 

Patents and Proprietary Rights

Patent protection covering CR1-based compounds is extensive. Among others, the company holds patents or licenses to patents on CR1 (including sCR1) covering its composition, its use in treating disease, its use in combination with other drugs and means for its purification and production. The company also has filed a patent covering compounds comprising sCR1 and an adhesion-inhibiting molecule. Such compounds may, in certain clinical settings, possess an additional capacity of binding to the walls of blood vessels damaged by the effects of inflammation. This action both localizes anti-complement activity to where it is needed and helps protect the damaged site from further injury by inflammatory cells.

 

Commercial Relationships

TP10 was developed jointly by T Cell Sciences and SmithKline Beecham from 1989 to 1994. In February 1995, T Cell Sciences regained all rights to the drug still held by SmithKline Beecham and now has worldwide rights, outside of Japan, to develop, manufacture and market TP10. In Japan, SmithKline Beecham and Yamanouchi continue to retain co-marketing rights for the compound.

In October 1997, T Cell announced the first of what we hope to be a series of collaborative agreements for our complement program. This agreement with Novartis Pharma AG, the worldwide leader in the transplantation field, is for the development of TP10 for use in xenotransplantation (animal organs into humans) and allotransplantation (human to human). T Cell will receive annual option fees and supplies of TP10 for clinical trials in return for granting Novartis a two-year option to license exclusive worldwide rights (except Japan) to TP10 for the specified indications. Should Novartis exercise its option to license TP10, it will make an equity investment in T Cell, and provide licensing fees and milestone payments based on the attainment of certain goals. The combined option and license is valued at up to $25 million. T Cell may also receive research funding in addition to royalty payments on eventual product sales.

In 1996, T Cell granted the drug delivery company Cytotherapeutics, Inc. a non-exclusive license covering certain patent rights to CR1 for use in their encapsulated-cell products for the delivery of drugs to the central nervous system. T Cell Sciences received a payment upon the signing of the agreement, and will receive future milestone and royalty payments.

TP10 has the potential to be the flagship product in a new class of therapeutics called complement inhibitors. With the development of complement inhibitors, it may at last be possible to address a major cause of inflammatory tissue damage in critical medical conditions with previously unmet therapeutic needs.

Updated December 3, 1997


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