Prospective Budget

The prospective budget outlined here is directed primarily toward the research, keeping in mind that the administrative costs will be supported as well.  By outsourcing the research, Immugen's overhead will be kept to a minimum, particularly in the early stages of funding.   Dr. Massey has experience in the successful "virtual" development of drugs.  By concentrating on core capabilities and outsourcing the components that can be performed effectively by contract research organizations (CROs) and academic researchers, Immugen can make the most of every dollar without spending money on unecessary infrastructure (e.g., rent, utilities, etc.) that does not add value in advancing the drug candidates.  We promise that we will undertake our research in the most transparent manner.  By supporting our research, you will have the right to know exactly how your money is being spent.  Immugen is a different type of pharmaceutical company, and we will proudly prove it.

Synthesis

Scale-up synthesis for small animal studies:  $1,000.00 per gram of material for 20 grams of each of the two lead compounds.  This price will drop significantly with the increased amount to be synthesized.

ADME/TOX

The initial screening protocols for ADME/Tox will determine which of the two drugs will emerge as the lead compound. 

Formulation

Once the lead compound is identified, it will undergo testing for the appropriate formulation, i.e., tablets, nasal spray, vaginal or rectal suppositories.

In-vitro Studies

Macrophage chemotaxis and lymphocyte homing studies. (UTMB)

In-vivo Studies

Influenza studies - $10,000.  These studies will be performed by Jiri Mestesky and his colleagues at the University of Alabama - Birmingham (UAB).

Pig-tailed macaques $25,000 per animal plus husbandry.  Minimum of 12 animals for the HIT study (six treated with the ARVs and CBs and six treated with ARVs and no CBs).  These studies will be conducted by Preston Marx, Ph.D., at the Tulane Primate Center.

Regulatory Affairs

As Dr. Massey has extensive regulatory experience, Immugen will perform as many regulatory functions "in-house", saving precious resources for the conduct of the development program.  Utilizing Immugen's in-house expertise will save a significant amount of money that can be applied toward other essential tasks.

 Pre-Clinical IND-Enabling Toxicology Program

In order to perform human clinical research, the drug candidates have to be shown to be safe in animals.  Once proven safe in animals, an Original Investigational New Drug Application will be submitted to FDA.  FDA approval of the IND allows for a drug to be shipped interstate for approved human studies.  The IND-enabling toxicology program is estimated to cost approximately $1.5 million and can be completed in 10 months.

Phase I Clinical Trial

Initial human clinical studies are designed to confirm safety in healthy adult volunteers.  These studies will delineate the actions of the drug candidates in the body.  The studies will focus on identifying metabolites, how the drugs are distributed in the body, how they're eliminated from the body and their safety.  These studies can be conducted in approximately six months at a cost of approximately $1 million.

Phase II Clinical Trial

These studies are designed to demonstrate that the drug candidate is effective and provide the basis for more extensive clinical testing.  The studies provide information on the proper doses to be employed and the characteristics of their clinical response that is of benefit therapeutically.  The costs of these studies vary, depending upon the disease targeted.  An approximate ballpark estimate of their costs would be in the $2-3 million range.

Phase III Clinical Trial

These studies form the basis for FDA approval, and their design and conduct resemble the clinical conditions in which they will be utilized.  FDA requires that two adequate and well-controlled trials show the drug candidates to be safe and effective for marketing approval.  These studies are very expensive and accurate estimates of their cost are not feasible at this time.  However, it is reasonable to expect the costs to be in the tens of millions of dollars.

Summary

Drug development is a costly endeavor.  However, you can be assured that Immugen will be as efficient as possible in the development of its drug candidates.

 

 

 

Committment to Basic Research

Immugen is committed to basic research which we hope will lead to a greater understanding of the cannabinoid class of drugs, and ultimately, to the development of a useful alternative to marijuana for the general public’s need. This should not diminish the perceived good derived from marijuana use, but establish a scientific basis for its use and ultimately provide a route of administration of a non-psychoactive analog which is more predictable and acceptable to the regulatory agencies world wide.

Grant Proposal Award Process

This page will be for the grant proposal award process, which will be described in greater detail as time goes on and funding becomes available. Suffice it to say that Immugen is committed to conducting and supporting research through a grant process similar to other philanthropic and governmental agencies. In addition to an internal review process which will be conducted by the Scientific Advisory Board, proposals can be approached in a collaborative manner similar to that seen in study sections and in the development of open-source software in the computer industry.

Unrestricted Use of  L759,656 and L759,633

Although there are a variety of CB2 specific ligands available for research purposes, most researchers continue to use THC, CP 55,940 and WIN 55,212-2, which are non-selective agonists for both the CB1/CB2 receptors. This contributes little to the development of the cannabinoid class of drugs devoid of psychoactive effects. Immugen has identified two compounds, L759,656 and L759,633, which were developed by Yves Gareau, et al., at  MerckFrosst, Canada, in 1996.  They are non-proprietary in nature but claimed by Immugen for a variety of uses in continuation and continuation-in-part patent applications based on the originally issued patent. Independent studies have established that these are excellent ligands to the CB2 receptor but they have not been utilized in other research to date. Toward this end, Immugen will make both compounds available to the research community without restriction, once we have been able to scale up the synthesis. In the meantime, we encourage our fellow cannabinoid researchers to include these two compounds in their research grant application process, since they are readily available through Tocris Biosciences.  Contrary to popular opinion, they are not controlled substances and will not require the lengthy process required by the DEA to acquire these compounds.

The research program can be divided easily into two basic areas: immune dysregulation caused by infectious diseases and immune dysfunction caused by inflammation.  In the  former, the main focus will be on HIV disease and influenza. In the latter, the emphasis will be on atherosclerosis, inflammatory bowel diseases and multiple sclerosis; however, other autoimmune diseases can be studied depending on the level of funding.

The Endocannabinoid System

 

As an herbal medicine, marijuana has been used for thousands of years for a variety of medical conditions. However, it was not until the 1970s that its effects on the immune system were first noted in terms of inhibition of lymphocyte function and macrophage activity, as measured by the inhibition of macrophage migration inhibitory factor (MIF). Over the next 40 years, it became clear that THC, the psychoactive component of marijuana, exerts its influence on the immune system by activating specialized receptors, Type II cannabinoid receptors (CB2), found on the membranes of every specialized type of cell in the immune system. These receptors are part of a larger class of receptors known as G protein-coupled receptors (GPCRs).  They bind substances produced outside the cell.  Once the receptor is activated, it relays a signal through an intracellular network, a process known as signal transduction.  This process directly affects the expression and activity of other receptors and ultimately results in the translation of the target cells’ genes to produce proteins.  These proteins further influence the outer environment in response to the original signal.  In the case of the CB2 receptor, it binds a variety of substances produced by the cells themselves -- specialized fatty acids or lipids, known as endocannabinoids -- as well as plant-derived compounds (cannabinoids), for which the system is named. It is currently thought that activation of the CB2 receptors produces a counter-regulatory response to the initial activation of the immune system, an inflammatory response, in order to restore homeostasis.  Hence, the cannabinoids are considered anti-inflammatory  in nature by facilitating the resolution of inflammation through down-modulation of the immune response, which is accomplished through activation of the CB2 receptors found on every type of immune cell.

Receptor Expression

However, the expression of these receptors varies according to cell type.  The greatest number are found on the antigen-presenting cells (APCs), and the least are found on the T lymphocytes. However, since the APCs typically make the first encounter with a threat,  process the antigen and present it to the T lymphocytes, it is now thought that activation of the CB2 receptors on APCs may be more influential on the outcome than activation of the CB2 receptors on the lymphocytes themselves, especially since it has recently been shown that the receptors are not expressed on the T lymphocytes unless they have been activated. Nevertheless, the overall reduction of anti-inflammatory proteins by APCs in concert with the lymphocytes is ultimately beneficial to the host.

HIV Disease

In the context of HIV disease, recently published research showed that CB2 ligands could inhibit the migration of macrophages towards the trans-activating (tat) protein of HIV and concluded:

 “…the immunosuppressive and anti-inflammatory properties of select cannabinoids may have         profound therapeutic potential in moderating HIV-associated immunopathology, including microglial activation, chemokine/cytokine dysregulation, and monocyte infiltration in the CNS.”

Immugen will continue to support research in this area and seek an early indication for the prevention and treatment of AIDS-related dementia. Additionally, the inhibition of immune cell migration and function has a potential application as a topical agent to prevent the transmission of the virus at the site of entry either vaginally or rectally.