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<sup>177</sup>Lu-PSMA-617 Questions and Answers

177Lu-PSMA-617 is a radioligand therapy (RLT) being developed by Endocyte that utilizes a high affinity targeting ligand to direct potent radiotherapy to prostate cancer cells. The specific targeting of this therapy comes from the “ligand” portion of the RLT, which is a small molecule designed to bind to Prostate Specific Membrane Antigen (PSMA) a protein highly expressed on the cell surface of most prostate cancer cells but absent on most normal cells. The PSMA targeting ligand in 177Lu-PSMA-617, is chemically attached to therapeutic radioactive particles called Lutetium-177 (177Lu), which releases energetic beta particles to precisely deliver cell killing radiation to the site of disease. Unlike traditional external beam radiotherapy, 177Lu-PSMA-617 is administered as a systemic injection where it can directly target multiple sites of PSMA-positive prostate cancer throughout the body, including the bone and soft tissue, while bypassing the PSMA-negative healthy cells. The expression of PSMA prior to treatment with 177Lu-PSMA-617 can be determined using whole body PSMA-directed imaging, allowing for personalization of treatment so that the best course of therapy might be selected. It is estimated that approximately 80% of men with metastatic castration-resistant prostate cancer (mCRPC) express PSMA on their cancer cells.
PSMA is a cell surface protein highly expressed on prostate cancer cells, with limited and lower expression in some normal tissues. The expression level of PSMA in these tissues is reported to be several hundred-fold lower than the level found on prostate cancer cells (Ghosh, 2004). It's this selective high expression in prostate cancer that has made it a valuable target for both diagnostic and therapeutic development. PSMA-PET (Positron Emission Tomography) agents have demonstrated significant tumor uptake relative to background, highlighting the specific targeting that is available for radioligand therapies (RLT) directed to this target. Using patient selection criteria involving measures of PSMA-positive disease burden, Dr. Michael Hofman presented data at the 2017 ESMO conference that showed ~85% of mCRPC patients screened met the definition of PSMA-positive for his study of 177Lu-PSMA-617.
Most previously developed PSMA-targeted agents were antibody-based or small molecules delivering chemotherapy, including Endocyte's EC1169. 177Lu-PSMA-617 is the first small molecule to deliver the cell killing radio-isotope (Lutetium-177) to diseased cells in mCRPC. The isotope Lutetium-177 is also used in Lutathera®, a recently approved therapy for the treatment of neuroendocrine tumors. The clinical results to date for 177Lu-PSMA-617 have been compelling and consistent across numerous, independent investigator initiated studies, and a prospective study conducted in Australia by Dr. Michael Hofman. Reported clinical activity includes prostate-specific antigen (PSA) reduction of >50% in between 40 and 60% of patients across multiple studies. A 71% response in soft tissue disease (as measured by RECIST criteria) was demonstrated in the 30 patient Australian prospective study as presented by Dr. Hofman at ESMO in September 2017 (see Hofman ESMO 2017). These results compare favorably to those observed for approved agents in even earlier lines of therapy.
There are numerous references in the scientific literature to the correlation of PSA response in mCRPC and overall survival (Fuerea 2016, Xu 2015). Drugs recently approved in 2nd line mCRPC demonstrated PSA response rates of approximately 30% on average (>50% reduction). In contrast, the most recent clinical study failures in this space recorded PSA response rates of between 6 and 13% (see Company Presentation). Importantly, PSA response for 177Lu-PSMA-617 therapy is also supported by soft tissue tumor shrinkage (RECIST response criteria), 45% overall response in the German multi-center study (Rahbar 2016) and 71% in the Australian study. The Australian study utilized a refined approach to select patients which may explain the higher response rate.
177Lu-PSMA-617 appears to be targeted and well tolerated at the current regimens and doses. Although extensive use of 177Lu-PSMA-617 has occurred in the clinic since 2014, safety monitoring has mainly been conducted through monitoring blood samples. A recent prospective clinical study showed the incidence of drug related grade 3/4 neutropenia, anemia and thrombocytopenia were 7%, 7% and 13% respectively. The only other grade 3 or 4 drug related toxicities were fatigue and bone pain in 3% of patients. Xerostomia (dry mouth) is also a common side effect – grade 1/2 and reversible (see Company Presentation).
177Lu-PSMA-617 has been developed to date through compassionate use studies in hundreds of mCRPC patients and more recently in prospective clinical studies. Because of the significant amount and consistency of 177Lu-PSMA-617 safety and efficacy data generated to date in over 300 patients, we expect to move directly into a pivotal Phase 3 study. We anticipate meeting with FDA to discuss our plan for a pivotal study in Q1 2018, and plan on starting a Phase 3 study in the first half of 2018.
Importantly, the most recent radiotherapy to launch, Xofigo (marketed by Bayer), has been a commercial success (expected to exceed $400 million in revenue in 2017), and it continues to grow at a healthy rate as familiarity with radiotherapies and development of referral networks have been established now in prostate cancer. In fact, Decision Resources Group forecasts Xofigo to reach over $930 million in annual revenue by 2024, despite the fact its label is limited to bone-only metastases. A second radiotherapy, Lutathera, just received approval in Europe for neuroendocrine tumors, and Wall Street consensus estimates for that therapy exceed $500 million peak annual revenue for that indication (with scenarios to $1.5 billion annually). Two radiotherapies that did poorly commercially were launched in the early 2000s, when referral patterns between medical oncologists and radiologists were not yet established. Further, those older therapies were monoclonal antibodies, a fundamentally different technology with different safety and efficacy profiles. As evidenced by Xofigo's success and Lutathera's consensus forecast, we believe the success of radioligand therapies (RLTs) launching today will be driven by the strength of their clinical data and not by market barriers between specialists.
177Lu-PSMA-617 is a radioligand therapy (RLT) targeting a radioactive warhead, Lutetium-177 (177Lu), to PSMA-expressing tumor cells in prostate cancer. The PSMA targeting ligand, PSMA-617, is chemically attached to therapeutic radioactive particles called Lutetium-177, which releases an energetic beta particle to precisely deliver cell killing radiation to the site of disease. Unlike 177Lu-PSMA-617, Radium-223, or Xofigo®, is not a PSMA-targeted therapy. PSMA is a protein that is highly expressed on the cell surface of most prostate cancer cells but largely absent on most normal cells. Importantly, PSMA is expressed on both diseased bone lesions and soft tissue lesions. Approximately 50% of post-chemo mCRPC patients have soft tissue metastases. Because of Radium-223's chemical similarity to calcium, its uptake (and therapeutic activity) occurs in bone lesions and is therefore only indicated for patients with disease restricted to bone metastases (not soft tissue).
About 100,000+ men die annually from mCRPC in the seven major markets (US, Japan, Germany, France, Italy, Spain, UK) and an estimated 80% of them have PSMA-positive tumors. So approximately 80,000+ patients today are potential candidates for PSMA-617. Assuming a price near that of similar therapies, the current 2017 market size estimate is roughly $5 billion. As potentially first to market with a PSMA targeted agent, Endocyte projects this opportunity as potentially greater than $1 billion at peak in these seven markets in the late stage of the disease.
This was a competitive transaction with market driven terms. Taken together, the $12m upfront, equity, and the milestone and royalty package are similar to comparable transactions of assets at a similar stage with compelling Phase 2 data.
No additional payments are owed to ABX before access to results of the Phase 3 study are known. The $160 million in potential one-time milestone payments owed to ABX include $25 million in milestones related to regulatory filing and regulatory approval of PSMA-617 in certain territories and $135 million in commercial milestone payments.
Yes, there is sufficient availability of Lutetium-177 to meet our needs. There are several manufacturers of cGMP grade Lutetium-177 available today. Endocyte has identified acceptable sources of Lutetium-177 in North America, Europe and Australia. Based on the favorable nuclear characteristics of this radionuclide, Lutetium-177 is considered an attractive choice for development (Pillai & Knapp, 2015)
Radioligand therapy (RLT) is administered by a radiation oncologist or nuclear medicine physician in a designated clinical setting. Treatment is given by a short intravenous infusion administered once every four to six weeks. Mild nausea may be experienced on the day of treatment so anti-nausea medication can be given shortly before the PSMA-617 injection. Patients are asked to maintain a good fluid intake on the day of treatment but sometimes doctors may prefer that their patients receive a short 'drip' to ensure a good urine output after therapy. In the US, the patient is generally allowed to leave the hospital a few hours after therapy as an outpatient procedure. Patients may experience a different length of stay in the hospital depending on the practices in the country of administration. (J Med Radiat Sci. 2017 Mar; 64(1): 52–60)

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