(I would appreciate help in analyzing this report on its scientific/medical merits. It certainly doesn't sound bullish for SPPI. Does anyone here know about Alpharadin or follow Algeta?)
Bayer’s Bold New Bet Fails to Rain on Spectrum Pharmaceuticals
Posted on September 3, 2009 by Michael Becker
By Michael D. Becker
Despite recent progress and the availability of novel therapies, radiation is still an effective tool in the war against cancer – as it has been for more than a century. The original and still predominant mode of administration is via external methods wherein a radiation source is directed at the intended target or region. Unfortunately, this “outside in” approach has the drawback of causing collateral damage to healthy organs and tissues that lie on either the path between the source and the target or beyond the intended target on the “exit” pathway.
In the 1990s, the U.S. Food and Drug Administration [FDA] cleared for marketing the first intravenously delivered, particle emitting radionuclides for the treatment of pain arising from the spread of cancer to bone. Termed Systemic Targeted Radionuclide Therapy (STaRT), this new approach offered the promise of selectively irradiating disease sites while sparing normal tissue. Metastron® [strontium-89 chloride injection] was introduced in 1993 and Quadramet® [samarium-153 EDTMP] was later introduced in 1997.
In 2003, the FDA cleared for marketing two different radioactive labeled monoclonal antibodies for the treatment of patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin’s lymphoma [NHL]. Both of these STaRT products utilize monoclonal antibodies that target an antigen expressed by certain normal and malignant B-cell lymphocytes. However, Zevalin® [ibritumomab tiuxetan] employs yttrium-90 as its therapeutic payload, while Bexxar® [tositumomab] uses iodine-131.
Despite great promise and STaRT’s established safety and efficacy, a July 14, 2007, article in the New York Times stated that only 10% of patients who are suitable candidates for the drugs ever receive treatment. Spectrum Pharmaceuticals, Inc. (SPPI) reported that U.S. sales of Zevalin were $11.4 million in 2008; while a similar non-radioactive product Rituxan® [rituximab] is a top-selling cancer drug by Genentech and Biogen Idec, Inc. (BIIB), with reported U.S. sales of $ 2.6 billion in 2008.
The lack of commercial success for existing STaRT products may be due to a mixture of clinical and commercial factors, including the following:
Clinical considerations
Half-life, or the amount of time required for a given amount of radionuclide to lose 50% of its strength or activity
In general, a half-life of 10 days or less is considered optimal, as longer half-lives may create waste management issues and clinically, are more likely to show toxicity problems.
Particle range
Higher particle ranges may result in greater damage to surrounding normal tissue, leading to side effects such as myelosuppression.
Specificity
Some radionuclides, such as strontium-89, have general disease-targeting properties, while others are conjugated to antibodies or other carriers to reach the intended target.
Commercial considerations
Production
Radioisotopes utilized for STaRT are produced commercially in nuclear reactors, cyclotrons or linear accelerators, and radionuclide generators, the selection of which can impact the cost-effectiveness of manufacturing.
Shipment
Radionuclides that have very short half-lives or that require extensive shielding as a result of high-energy gamma ray emissions [eg, iodine-131] create logistical issues for shipment and handling and may even require a local production unit close to the treatment center.
Administration
Marketers often assume that oncologists’ decisions about therapy are driven purely by the scientific data. While medical oncologists are the key prescribing audience for marketed STaRT therapies, most aren’t licensed to administer radiopharmaceuticals – resulting in patient referrals to radiation oncologists and/or nuclear medicine physicians. Therefore, these physicians may not be economically incentivized to prescribe products that they are not paid to administer.
Reimbursement
Reimbursement by the Centers for Medicare and Medicaid Services [CMS] and private insurance carriers is critical to the commercial success of any product. In a letter by GlaxoSmithKline plc (GSK) to CMS regarding changes to the Hospital Outpatient Prospective Payment System [HOPPS], the company indicated that the proposed 2008 payment rate for Bexxar “results in a reimbursement rate that is approximately 50% below hospitals’ actual acquisition cost for the therapy.”
While some commercial considerations, namely administration and reimbursement, still need to be addressed, “next-generation” STaRT product candidates appear to address many historical clinical considerations and could ultimately fulfill the promise of this therapeutic class.
For example, Algeta ASA (OSE: ALGETA) is developing Alpharadin, the first in a new class of STaRT therapies based on the alpha-emitting radionuclide radium-223. Phase 2 studies in patients with hormone-refractory prostate cancer [HRPC] have already demonstrated that Alpharadin can prolong patient survival, improve quality of life and offer a benign safety profile. A Phase 3 trial is underway to confirm Alpharadin’s efficacy and safety as a targeted treatment for bone metastases in patients with HRPC.
Radium-223 appears to offer the perfect mix of clinical characteristics (see table 1 for a comparison of STaRT products). It has an 11.4 day half life, which is significantly shorter than the 50.6 day half-life for strontium-89, but not too short to create logistical issues with shipment. Further, radium-223 has an extremely short particle range of 0.04 millimeters, which is equal to approximately 2-10 cell diameters. This likely explains Alpharadin’s benign toxicity profile.
Table 1: comparison of STaRT products
Year Introduced Product Indication Radioisotope Half-life Max Particle Range in Tissue
1993 Metastron®
Treatment of bone pain arising from cancer Strontium-89
50.6 days
8.00mm
1997 Quadramet®
Samarium-153
1.9 days
3.00mm
2003 Bexxar®
Treatment of non-Hodgkin’s lymphoma Iodine-131
8.0 days
2.00mm
2003 Zevalin®
Yttrium-90
2.7 days
12.00mm
Phase 3 trial underway Alpharadin
Treatment of bone metastases in hormone-refractory prostate cancer Radium-223
11.4 days
0.04mm
Lending credibility to the future of next-generation STaRT products, Algeta today announced an $800 million global agreement with Bayer AG for the development and commercialization of Alpharadin. In view of the fact that Bayer currently markets Zevalin outside of the U.S., this news could be interpreted as either good or bad news for investors betting on an acquisition of Spectrum Pharmaceuticals.
The bullish case is that Bayer is making a fresh $800 million investment in the field of STaRT, which could lend support to a consolidation of Zevalin marketing rights by Bayer. However, the bear case is that Algeta has already demonstrated in vivo the potential of linking alpha-emitting radionuclides to existing monoclonal antibodies, including rituximab, which could ultimately pose quite a competitive threat to earlier-generation STaRT products like Zevalin. In view of recent 52-week highs for Spectrum Pharmaceticals, however, it appears for now that investors are opting for the bullish thesis.
Bladerunner
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