Therapeutic Target Considerations

Therapeutic target or treatment hypotheses submitted to the FDA as part of inves-tigational new drug (IND) applications

ITABLE 3.4. Historical data on clinical trial success rates as compared to clinical leverage strategy

Clinical

Historical Data

Clinical Leverage Strategy

For Every 4 NDCs (j)

Procession Rate

Fraction

Projected Procession Rate (Fraction)

Clinical

For Every 4 NDCs (j)

Fraction

Trial

Tested

(Products)

Percentage

Are Tested

Indications

Product

Phase I

! ! ! !

4/4

100

11 i i

4/4

1/1

Phase II

! ! !

3/4

75

ttt

3/4

1/1

Phase III

! I

1.5/4

27.5

1.

1.5/4

1/1

FDA

!

1/4

25

t

1/4

â– TABLE 3.5. New drug candidates in human clinical trials using clinical leverage strategy

New Drug Candidate

Indications Being Tested

Clinical status"

(platelet activation factor-AH)

ARDS' Asthma

Post-ERCP' pancreatitis Severe Sepsis

Phase II Phase II Phase II Phase III

ICOS/Suncos Corp

IC351

Male erectile dysfunction Female sexual dysfunction

NDA filed Phase II

ICOS/Lily

LeukArrest (MoAb Hu23F2G)

Hemorrhagic shock Ischemic stoke Multiple sclerosis Myocardial infarction

Phase II Phase III Phase II Phase II

ICOS

Denileukin diftitox

Cutaneous T cell lymphoma

Recurrent/persistent lymphoma Non-Hodgkin's lymphoma

Phase II Phase III Phase II

Ligands

Iodine-131 Anti-B1 Antibody

Non-Hodgkin's lymphoma

Chronic lymphocytic Leukemia

Mantle cell lymphoma

GlaxoSmithKline

Bevacizumab + other drug

Breast cancer

Colon and rectal cancer

Phase III Phase II

"As of 2001.

'Abbreviations: ARDS, Acute respiratory distress syndrome;ERCP, Endoscopic retrograde cholangiopancrea-topography.

combination

"As of 2001.

'Abbreviations: ARDS, Acute respiratory distress syndrome;ERCP, Endoscopic retrograde cholangiopancrea-topography.

eventually become part of the new drug application (NDA) package that supports usage and treatment indications for each new molecular entity seeking approval in the United States. For each therapeutic target or indication, the sponsoring pharmaceutical company must file separate IND applications and evaluate the efficacy and safety of the NME independently in each case. Therefore it is critical early in the process for a drug company to consider the therapeutic target with the highest impact on therapeutic outcome and return on investment.

With the introduction of molecular cloning and expression, automation, and computing power, it became even more important to choose a target disease and the right kind of molecule early in the course of development. Clearly, the selection of a disease target based on an in-depth understanding of the pathology and potential points of intervention will aid therapeutic evaluation. An additional consideration is the need for a clearly measurable therapeutic outcome or end point, based on clinical or laboratory measurements, that reflects efficacy and toxicity. Multifaceted disease states with ill-defined outcomes will be more challenging. Some of these issues will be discussed in the context of clinical testing of biopharma-ceuticals (see Chapter 4, Section 4.3).

The choice of therapeutic target may vary from drug company to drug company depending on its unique resources, such as patent-protected technology and expertise in certain biological processes that lead to disease. The specific molecular characteristic of the biopharmaceutical for the therapeutic target can take the form of a protein, peptide, or antibody. These choices will have a great impact on the success of development and the time it takes to transform lead candidates into therapeutic products.

In this section we will discuss the rationale for the successful development of well-characterized biotechnology products, including (1) synthetic peptides of less than

20 amino acids, (2) recombinant DNA-derived macromolecules, and (3) monoclonal antibodies and derivatives. A drug company's strategy involves either the improvement of an already available biologic (e.g., insulin) or the development of a novel one.

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