The term theragnostic test is herein defined as a molecular test that is integrated into the drug development process so as to guide patient selection and drug treatment protocols. Subtle genotypic or phenotypic variations, including nucleotide or amino acid substitutions at the level of DNA, RNA or protein, are measured by this molecular test.

PIKAMAB is initially developing two proprietary MAb theragnostic tests: ADCC Therasight; and Lupus Therasight‡:

• ADCC Therasight measures the ADCC profile of a patient before, during, and/or after treatment. The test quantifies the patients’ ability to respond to MAb therapies which use ADCC as the major mechanism of action.
• Lupus Therasight determines the progression and severity of the disease in SLE (systemic lupus erythematosus) and lupus nephritis patients before, during, and/or after treatment.

Use of these theragnostic products offers the much needed critical guidance in drug development and treatment protocols by providing a powerful framework to customize therapies to all patient groups because these tests are clearly correlated either to the mechanism of action (MOA) by which therapies work or to the underlying mechanism of disease progression. Thus, excellent therapeutic outcomes can be achieved in all patient groups.

ADCC Therasight is used to measure the physiological ADCC profile in a patient before and after treatment with MAb therapies. Based on a series of assays, a cumulative ADCC Therapeutic Index is generated for a given patient. This index provides biopharma companies, payers, and physicians the critical guidance as to how well each patient will respond to a MAb therapy.

ADCC Therasight provides critical information as to when (and whether) to administer MAb therapies after the patients have been treated with CHOP or radiation therapies. For example, a patient who has been treated with chemotherapy (CHOP) or radiation therapy just before MAb therapy can have a very low ADCC Therapeutic Index because of the simultaneous depletion of immune cells. Thus, determination of mere genetic polymorphisms (VF158 polymorphism in FcGR-3A; HR¹³¹ polymorphism in FcGR-2A) in patients will not provide an accurate determination of the therapeutic index in a given patient. For example, a patient in Group-1, as determined by VV¹⁵⁸ in FcGR-3A and HH¹³¹ in FcGR-2A, although expected to have excellent therapeutic response rate can still have poor ADCC Therapeutic Index if he had been recently subjected to CHOP or radiation therapies.

The following marketed MAbs are expected to benefit by incorporating the ADCC Therasight: rituximab (Rituxan), trastuzumab (Herceptin), cetuximab (Erbitux), and alemtuzumab (Campath). In the case of rituximab monotherapy in B-NHL patients, this stand-alone test could provide the necessary theragnostic information. However, for the administration of Erbitux and Herceptin, this test would have to be combined with K-RAS test and HER-2 test, respectively.

IgG₂ MAb therapies can potentially exert their therapeutic effect by ADCC, by binding to FcGR-2A receptors present on macrophages and neutrophils. If so, patients with HH¹³¹polymorphisms are expected to have better therapeutic response rate than the RR¹³¹patients. ADCC Therasight can determine whether or not an IgG₂ MAb therapy uses ADCC as a predominant mechanism of action.

Representative Publications:
FDA holds court on post hoc data linking KRAS status to drug response.
Mack, GS., Nature Biotechnology 27:110-112 (2009)

Novel risk-sharing scheme puts the spotlight on biomarkers.
Hughes, B., Nature Reviews Drug Discovery6:945 (2007)

Looking forward, looking back.
Editorial Commentary. Nature Biotechnology26:475 (2008)

The emerging role of pharmacogenomics in biologics.
Lacana et al., Clinical Pharmacology & Therapeutics82:466-471 (2007)

Payers aim to rein in specialty-drug spending: employers, health plans, PBMs push for legislation.
Idea: ‘Pay for Performance’.
Chase M., Wall Street Journal page:B1, March 20, 2008.

Gene test for Erbitux, cancer could save $604 Million.
Lauerman, J., BloombergJanuary 13, 2009.
http://www.bloomberg.com/apps/news?pid=20601103&sid=abNqlkdPZxSw&refer=us

Strategy
The theragnostic test can act as a gatekeeper in a crowded market landscape, ensuring that the right patients receive the most appropriate treatment. Moreover, the development of a combination product (Drug + Theragnostic Test) provides market exclusivity and added patent protection to the drug, and thus can command higher pricing premium.

PIKAMAB will initially commercialize these theragnostic products with partners whose MAb candidates are in clinical development and whose MAb therapies are currently available on the market.

By partnering with biopharma companies, PIKAMAB’s theragnostic (Tx) tests will be co-developed with MAb candidates, possibly as combination products (MAb+Tx). In addition, based on systematic retrospective or prospective analysis of clinical trials, these tests will also be developed as stand-alone products to be incorporated into drug treatment protocols for already approved MAb therapies such as Rituxan, Erbitux, Herceptin, Campath, and Remicade. As necessary, these tests will be customized to individual MAb therapies.

R&D costs for new biopharmaceuticals (including the costs of failures and time costs) have been estimated to average in excess of $1.2B. Theragnostics-guided MAb development can potentially reduce drug development cost and time. For several strategic reasons, biopharma companies may need to embrace the stratified medicine paradigm because the payers in the U.S., as well as Europe and Canada are gearing up for pay-for-performance model. A case in point is the label restriction by EMEA and Health Canada for the administration of Erbitux^® and Vectibix^® therapies only to the K-RAS-wild type colorectal cancer patients as determined by the K-RAS genetic test.

PIKAMAB is well positioned to advance the field of MAb theragnostics because of its proprietary IP position.

^‡: Both theragnostic tests will be developed as CLIA-certified tests which will be made available worldwide with testing locations in the U.S., and Europe. These products provide therapeutic guidance to several marketed MAbs by stratifying patients to predict response rates; thus, improved treatment outcomes can be achieved. This leads to higher pricing premium, market refinement, and market exclusivity for biopharma companies.