New Therapeutic Radiopharmaceuticals Drive Market Growth Worldwide
Nov 6, 2012
Investment in therapeutic radiopharmaceuticals increased by an order of magnitude during the past two years with serious commitment to the technology and definite plans to bring the new products in development to market. Many of the new products will be introduced in 2014-2016 with procedure growth averaging 40 50% per year initially. As the products demonstrate effectiveness, it will stimulate the pace of development and accelerate introduction of products in the pipeline. Therefore, sales are forecast to increase from $244.9 million in 2012 to $5,802.8 million by 2020.
Improvements in Imaging Technology
Continuing improvements in imaging technology for both SPECT and PET are allowing higher resolution and shorter imaging times. Radiopharmaceutical doses are also being pared down as a result of increased imaging efficiency. This makes nuclear medicine safer than many other imaging modalities that are threatened with excessive radiation and patient safety issues.
Delivering targeted radiation to malignant cells with therapeutic radiopharmaceuticals has significant advantages over conventional therapies. It allows one to seek out and destroy diseased cells while protecting healthy cells in the vicinity. In addition, the new generation of therapeutic radiopharmaceuticals employs more advanced targeting with antibodies and peptides linked to therapeutic isotopes that are optimized for each application. Researchers are also pursuing applications which benefit from the unique capabilities of therapeutic radiopharmaceuticals rather than overlapping existing oncology products.
There are 19 radiotherapy products that are either approved or in development. Many of the research products are being financed by international companies with significant resources and commitment to the success of these ventures. This establishes a new platform for many of these products since it provides a natural link between both U.S. and international markets.
Major Increase in International Investment
One of the most encouraging developments in the therapeutic radiopharmaceutical field is the recent growth in international investment in new products. This shows confidence in the clinical potentials of these products and the opportunity to develop a commercial platform that will sustain continued growth both in the U.S. and internationally.
Some of the important joint ventures are as follows:
- Alpharadin - Algeta-Bayer have a partnership to develop and commercialize Alpharadin for treating bone cancer. This product has completed Phase III trials and is on fast-track status with the FDA. Bayer has made a substantial investment with high confidence in the success of the venture.
- Lutathera –Advanced Accelerator Applications AAA), Saint-Genis-Pouilly, France. The company is sponsoring Phase III trials of Lutathera in the U.S. for treating neuroendocrine tumors. This is a late stage development with orphan drug and fast-track FDA status. This drug has been used in Europe for many years with successful results.
- Alpha therapy with lead 212, bismuth-212 for metastatic abdominal cancers including breast, colon, ovarian, gastric, pancreatic and endometrial. AREVA Med subsidiary of AREVA (the French nuclear energy conglomerate) is sponsoring development with major clinical oncology centers in the U.S.
- Lu-177-J591 for localized and metastatic prostate cancer. Atlab Pharma, Nantes, France has licensed the product and is in a joint venture with BZL Biologics, commercial subsidiary of Cornell Weill Medical Center. The J591 PSMA antibody has completed several successful clinical trials and is a strong contender in the prostate cancer therapy market.
New Milestone for Zevalin - Approval as a First-Line Therapy
The indications for using Zevalin and Bexxar were initially limited to refractory cases of non-Hodgkins lymphoma where patients did not respond to Rituxan or other chemotherapy. By the time Zevalin or Bexxar therapy was implemented, patients were so weakened by the progress of their disease as well as other therapy that their response to Zevalin or Bexxar was poor.
In 2009, Spectrum Pharmaceuticals acquired the rights to Zevalin and the company built an aggressive sales platform for promoting Zevalin to oncologists. The improved acceptance has already resulted in a doubling of sales for Zevalin.
In 2012, the FDA approved the use of Zevalin as a first-line therapy, which expanded the patient base and allowed the drug to be used in earlier stages of treatment when the prospects for survival are better. This improved the outcome for many patients and encouraged wider use of Zevalin.
Approval of Zevalin as a first-line therapy has also created a better platform for oncologists to adopt the drug as a standard-of-care in treating lymphoma patients. It has also helped patient advocate groups to better assist patients who are candidates for Zevalin. This is particularly important in implementing a new therapy where patient education is important in building confidence.
Approval as a first-line therapy will also help in market development for new therapeutic radiopharmaceuticals in the pipeline. These drugs will have the opportunity to demonstrate effectiveness with patients that are good candidates for this therapy prior to an exhaustive series of traditional chemtherapy which weakens the patient.
Eliminating the Bioscan Requirement to Simplify the Protocol
Spectrum was successful in eliminating the bioscan requirement for Zevalin. The bioscan was initially implemented to determine distribution of the drug prior to its use. It was implemented during the research phase to assure that the radiation risk to the kidneys and internal organs was within safe limits. As experience accumulated with the drug, it was clear that the approved dosing schedule based on body weight was safe and did not require validation every time the drug was used.
The bioscan requirement also entailed sending the patient to a specialized imaging facility in a hospital where control was transferred away from the oncologist. This was not good for the patient or the oncologist. Therefore, eliminating the bioscan requirement has allowed the oncologist to maintain control of the patient and assure continuity, while creating a better platform for utilizing Zevalin.
Improved Reimbursement for Therapeutic Radiopharmaceuticals
When Zevalin was introduced, reimbursement was in the range of $21,000 a dose, which included a dose of Rituxan as preconditioning. CMS has reevaluated the pricing of Zevalin and increased the reimbursement to $35,000, which is consistent with other chemotherapy drugs. This also acknowledges the cost of manufacturing and distributing the drug. The higher reimbursement benefits the oncologist who receives a handling fee of 4-6% of costs. Therefore, the higher approved cost allows the oncologist to recover a higher fee for handling and administering the drug.
With traditional oncology drugs, there are generally 4-6 fractions (individual infusions) for each round of therapy. Reimbursement for the therapy inclusive of all the fractions is generally about $50,000-$60,000. Therefore, the revised reimbursement is consistent with other chemotherapy. It also establishes a better price platform for similar drugs in development.
There has also been an increase in reimbursement for other therapeutic radiopharmaceuticals. Reimbursement for bone pain palliation agents was increased from $3,250 per dose to $7,555 per dose, an increase of more than 100%. This acknowledges the special nature of these drugs and the associated cost of producing and distributing them.
Therapeutic Radiopharmaceutical Pipeline Products
There has been significant progress in the development of therapeutic radiopharmaceuticals for treating solid tumors and disseminated malignancies such as lymphoma and leukemia. There has also been clearer focus on utilizing therapeutic isotopes that are optimized for each application. This has led to increased use of alpha emitters in treating blood borne tumors and metastases where tumors are circulating in the blood. Examples are actinium-225, bismuth-213, lead-212 and radium 223. Ingenious methods of delivery are being pursued where multiple isotopes in a particular decay chain are being used to extend the range of action.
In 2012, therapeutic radiopharmaceuticals achieved some important milestones. Clinical experience with Zevalin and Bexxar continued to improve in terms of disease-free survival for patients treated with these products. There have also been no side-effects or technical issues that might detract from their use. The challenge has been to make this therapy more visible to oncologists and their patients so that it might be used effectively in conjunction with other therapies. Considerable progress has been made in this direction with better understanding of the incentives necessary for clinicians to use these products. The improved outlook has stimulated the pace of research with similar radiotherapy products, which should lead to new market opportunities. Furthermore, several of the developmental products are on fast-track status with the FDA with some large Phase III trials underway that look very promising.
Optimizing the Selection of Therapeutic Isotopes
From a functional standpoint, therapeutic radiopharmaceuticals utilize receptor-based antibodies or peptides which are chemically bound to selected isotopes. These drugs can be targeted to certain tumors delivering a radioactive dose locally, while limiting the effect on surrounding healthy cells. In principle, the selected antibody or peptide is generally one that can reduce or limit cellular proliferation by virtue of its action on a specific antigen or cell surface receptor. When combined with a radioactive isotope, it offers a synergistic effect in destroying malignant cells.
As technology has progressed, the number of available therapeutic isotopes has increased, allowing selection of the most appropriate energy level and half-life for the specific application. Initially, there was a strong focus on utilizing isotopes that could be imaged to assure that targeting was successful. While this is still desirable in certain cases, researchers now find it more important to employ radioisotopes that have the right energy level to minimize side effects independent of an imaging capability. Since the radiation dose delivered is dependent on half-life of the radiopharmaceutical as well as its energy level, selection of a shorter half-life allows a higher energy level, which offers advantages in certain cases. One objective is to select an energy level that is consistent with the size of the tumor being treated. The larger tumors benefit from a higher energy level, such as yttium 90, whereas the smaller tumors are more effectively treated with lower energy level isotopes, such as lutetium-177 and alpha emitters that can be accurately targeted.
Alpharadin for Bone Cancer
Alpharadin is being developed by Algeta, (a Norwegian company) for treating bone cancer and cancers that have metastasized to the bone. The product is based on radium-223, which is an alpha emitter. Radium is a calcium analog that has a natural affinity for bone. This allows the product to be used without antibody or peptide targeting, simplifying the protocol.
The half-life of radium-223 is about 10.5 hours, which is adequate for handling and shipment. The decay chain for radium-223 has four alpha emitting elements and three beta emitting elements. The alphas have a very short range and can reach tumor cells that are in close proximity in the bone. The three betas in the decay chain are also available to reach cells that may be close but outside the range of the alphas. Therefore, the combination has a lot of advantages.
Alpharadin has been in development for some time and has completed several large clinical trials that have demonstrated both safety and effectiveness. Recognizing this potential, Bayer formed a partnership with Algeta in which Bayer has made a substantial investment in Algeta in return for sharing the profits from Alpharadin.
Algeta’s FDA submission for Alpharadin is now on a fast track based on a significant increase in survival time for bone cancer patients. Therefore, one can expect a rapid buildup in sales effort as soon as approval is granted.
Lutathera for Neuroendocrine Cancer
Lutathera is being developed by Advanced Accelerator Applications (AAA) of Saint Genis-Pouilly, France. Lutathera, also known as leutitium-177 DOTA-TATE, was developed by Dr. Eric Krenning and associates in The Netherlands and the drug has been extensively evaluated over a period of 15 years in major clinical centers in Europe. AAA acquired rights to the drug in a partnership with Dr. Krenning with the intention of commercializing it in the U.S. and other parts of the world. Lutathera is one of a group of drugs that is based on peptide receptor radionuclide therapy (PRRT). The peptide is targeted to one of the somatostatin receptors that are commonly expressed on most neuroendocrine tumors.
AAA has recently embarked on a major clinical validation program in the U.S. to obtain FDA approval for Lutathera. The company has commitments from 14 major medical centers to participate in a large Phase III trial that will form the basis for FDA approval. Since there is considerable experience with this drug and its safety and effectiveness so well established, it is likely that FDA approval will be granted fairly swiftly. The drug has also received orphan drug status, which should further accelerate the review process.
Actimab for Leukemia and Blood Borne Cancers
Actinium Pharmaceuticals is developing Actimab-A for treatment of acute myeloid leukemia and Actimab-B for bone marrow ablation and stem cell transplantation. These products are based on the use of the anti-CD45 monoclonal antibody BC8 which is in an advanced clinical stage. The CD45 antigen is expressed on most white blood cells and can be used to target these cells with an appropriate antibody linked to a therapeutic isotope. Actimab-B is also being developed to ablate bone marrow in preparation for stem cell transplantation. These products utilize the alpha emitting properties of actinium-225 coupled with a proprietary monoclonal antibody. Actimab-A has also been designed to treat acute myeloid leukemia where the diseased blood cells are destroyed by the action of the targeted antibody and the localized alpha radiation.
The company has investigators at 5 major medical centers (Memorial Sloan Kettering, Johns Hopkins, University of Pennsylvania Health System, Fred Hutchinson Cancer Center and University of Alabama Birmingham Cancer Center). This research has been ongoing for some time and has demonstrated both effective targeting and precise energy deposition using alpha emitters.
The company has been refinanced recently allowing an expansion of its research activities with dedication to commercializing these products. The company also has an impressive pipeline of other targeted alpha-emitting isotope products for treating metastatic cancers including colon cancer and prostate cancer.
Lead-212 Alpha Therapy for Metastasized Abdominal Cancers
The French nuclear energy conglomerate, Areva, has made a major commitment to developing radiotherapy products in the U.S. that will benefit from its expertise in the nuclear energy field. The company has established a subsidiary in the U.S., AREVA Med, to focus on developing therapeutic radiopharmaceuticals utilizing the company's resources in the nuclear field. As part if this effort the company acquired Macrocyclics, which specializes in the radiochemistry field with expertise in compounding and labeling medical isotopes with antibodies and peptides.
AREVA Med plans to develop state-of-the-art therapeutic radiopharmaceuticals for treating cancers that are resistant to conventional therapies. As part of this platform, they have selected a broad category of cancers that are responsive to Herceptin (HER2). This includes breast, ovarian, colon, gastric, pancreatic and endometrial cancers. Researchers will utilize alpha emitters such as lead-212 and bismuth 212 labeled with traztuzumab, which is an antibody that targets HER2 positive cancers.
Areva Med has contracted with the University of Alabama Radiation Oncology Center as its primary clinical site plus four other major oncology centers in the U.S. to conduct clinical studies within the framework of an FDA approved clinical validation program. This is a broad-based effort that will bring together the best clinical talents and scientific expertise in the radiopharmaceutical field with the resources and investment necessary to assure Areva’s objectives in this field.
Lu-177-J591 PSMA Antibody for Prostate Cancer
ATLAB Pharma (Nantes, France) and BZL Biologics (Cornell Weill Medical Center) signed an exclusive global licensing agreement for Lu-J591, a novel radiopharmaceutical in Phase IIB for the treatment of prostate cancer
The goal of the project is to develop a targeted radiotherapy drug with the unique ability to eradicate micro-metastatic disease at an early stage of cancer progression. They are confident that current trials will confirm the survival benefits of Lu-177-J591 at the micrometastatic stage of castrate resistant prostate cancer. The Agreement includes exclusive rights to manufacture, develop and commercialize this radiopharmaceutical product worldwide.
ATLAB Pharma SAS is a French biotechnology company based in Nantes. France. The company is developing a pipeline of targeted anti-cancer drugs including antibodies, Lutetium-177 beta-emitting radiopharmaceuticals and astatine 211 alpha-emitting radiopharmaceuticals.
Lu-J591 combines the humanized J591 monoclonal antibody targeting prostate-specific membrane antigen (PSMA) plus the Lu-177 radioisotope creating the first tumor-specific delivery system able to target radiation to malignant prostate cancer cells wherever they are in the body.
Indium-111-Pentetreotide for Neuroendocrine Tumors
Indium-111-pentetreotide is an effective form of radiotherapy for neuroendocrine tumors that are either localized or metastasized. One recent clinical study involved 112 patients that were treated over a period of 5 years with high dose indium-111 (up to 500 mCi) with very effective results. This product was developed by Biosynthema, which was formerly a division of Mallinckrodt. Biosynthema was recently acquired by AAA (Advanced Accelerator Applications) which also has rights to Lutathera (DOTA-TATE).
The indium-111 therapy utilizes the Auger electron which exerts its therapeutic effect over a very short distance and is very concentrated. Therefore, it is extremely safe and effective with tumors that are moderate in size (3 cm in size or less) and have only metastasized to one location.
At present, the product is being used on an IND (new drug development basis). It is likely that AAA and Biosynthema will file an NDA in the near future as soon as Lutathera is approved, which will create a positive platform for approval of the indium-111 product.
Yttrium-90 Clivatuzumab for Pancreatic Cancer
This product is being developed by Immunomedics and has completed several successful Phase II trials. The antibody has been shown to provide effective targeting for pancreatic cancer and exerts its therapeutic effect over a moderate range consistent with the beta emissions from yttrium-90. This therapy offers an effective option in cases where the pancreatic cancer does not respond to peptide receptor therapy such as Lutathera or indium-111 pentetriotide. Pancreatic cancer is generally difficult to treat depending on how extensively it has spread. Therefore, Y 90 clivatuzumab is an important addition to the armamentarium. Immunomedics is negotiating with several prospective partners to sponsor Phase III trials that would form the basis for an NDA submission with the FDA.
CycloSam for Bone Cancer
CycloSam is being developed by Isotherapeutics Group, which is the successor to Dow Chemical’s radioisotope business. Dow was in this field for many years and has a large portfolio of patents for therapeutic radiopharmaceuticals which was acquired by Isotherapeutics when Dow exited this field. One of Dow’s patents was for samarium-153 EDTMP, Quadramet for bone pain palliation. This product was licensed to Cytogen Corporation and was successful in gaining a strong market position in this segment.
Isotherapeutics is continuing to develop therapeutic products utilizing samarium and holmium for bone cancer and related applications building on the experience gained with Quadramet. Current efforts are directed toward a higher energy version of Quadramet that is suitable for cancer therapy going beyond bone pain applications. This has become possible because of an improved chelating agent for the radioisotope, DOTMP instead of EDTMP. The superior linker allows a higher level of radioactivity to be employed safely with samarium-153, expanding its capabilities for bone cancer applications. The new product CycloSam has performed well in clinical trials and should be successful in treating bone cancer.
Phospholipid Ether Tumor Targeting
Novelos Therapeutics is developing phospholipid ether (PLE) analogues that interact with lipid rafts, which are specialized microdomains within cell membranes. The technology provides selective targeting of cancer cells in preference to normal cells due to enrichment of lipid rafts in the cancer cells.
The basis for selective tumor targeting of the company's compounds lies in differences between the plasma membranes of cancer cells compared with normal cells. Cancer cell membranes are highly enriched in “lipid rafts” which are specialized regions of the membrane phospholipid bilayer that contain high concentrations of cholesterol and sphingolipids and serve to organize cell surface and intracellular signaling molecules (e.g. growth factor and cytokine receptors). Lipid rafts are portals of entry for PLE's which are linked to therapeutic molecules such as I-131 or imaging isotopes such as I-124 that is effective with PET.
It has taken a long time to recognize that therapeutic radiopharmaceuticals are not traditional pharmaceuticals although they must be used in a traditional oncology environment. Therefore, corporate sponsors have tried to position these products so that they can be used in parallel with traditional therapies, shifting the emphasis in favor of radiotherapeutics where there is a reasonable fit. As these products enter the mainstream, they will be integrated into the treatment regimens of clinical oncologists in an orderly fashion so that they can be matched properly with patient candidates. As experience increases with these products they will be used as the standard-of-care, which should create a positive platform for future growth.
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