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At the time of this writing, there are thirteen (14) drugs currently approved by the Food and Drug Administration for the treatment of prostate cancer. There are others which are in various stages of clinical development or review.  A number of these have been mentioned in earlier blog posts on this website. The National Cancer Institute (NCI) of the National Institutes of Health (NIH) has an excellent website (see also http://www.cancer.gov/cancertopics/types/prostate). A list of approved drugs is also given. Personally, I am finding it helpful to briefly list the drugs discussed in this website with a description of their potential uses and current developmental status. It is my intent to maintain this website listing as current as possible with new additions and developmental updates.

Therapeutic agents already approved by the FDA include:

1 – Lupron (Leuprolide Acetate); used to suppress the production of testosterone in androgen deprivation or hormonal therapy. Leuprolide falls into a class of drugs called luteinizing hormone-releasing hormone (LHRH) agonists. Others drugs in this class include goserelin (Zoladex), triptorelin (Trelstar) and histrelin (Vantas).

2 – Prednisone; used in conjunction with chemotherapy to reduce its potential side effects, inflammation and suppress the body’s immune response.

3 – Taxotere (Docetaxel); a second generation, synthetic taxane drug based upon compounds (Taxol) derived from the European yew tree and used as a potent and broad chemotherapeutic agent. In treating metastatic, hormone-refractory (resistant) prostate cancer, it may be used used in conjunction with other anti-cancer agents and prednisone. Taxotere may be combined with Carboplatin, Xeloda (see below) or Emcyt. It has also been used effectively combined with Avastin and Revlimid.

4 – Jevtana (Cabazitaxel); a new taxane (see taxotere) administered with prednisone and used to treat metastatic, hormone-refractory (resistant) prostate cancer in men who have already undergone chemotherapy. It was approved by the FDA in spring, 2010 for use in metastatic, hormone-resistant prostate cancer patients who have failed chemotherapy with docetaxel (taxotere). (Discussed in the May 7th, 2011 blog post and see http://www.cancer.gov/clinicaltrials/results/cabazitaxel0310).

5 – Zytiga (Abiraterone acetate); This once-daily, oral drug from Johnson & Johnson was approved in April, 2011 for use in men with metastatic, hormone-refractory prostate cancer who have failed docetaxel (taxotere) chemotherapy. Zytiga inhibits two distinct steps in the production of testosterone from cholesterol even in tumor cells themselves by blocking a cell membrane enzyme called CYP17A1.  Inhibiting one step (lyase) in the testosterone production accounts for the drug’s efficacy but inhibiting the other step (hydroxylase) leads to its side effects. (Therefore it might be advantageous to find a drug that would inhibit only the step that accounts for the undesirable side effects). Zytiga is co-administered with prednisone. For additional information, see Wikipedia.  (Discussed in Jan. 8th, May 7th, June 3rd, and Nov. 21st, 2011 blog posts).

6. Zytiga (abiraterone acetate)  in combination with prednisone is now approved in the U.S. to treat metastatic high-risk castration-sensitive prostate cancer (CSPC) Janssen Pharmaceutical Companies announced. The U.S. Food and Drug Administration (FDA) granted its approval in February 2018 following results of the Phase 3 LATITUDE trial which showed that the combo therapy reduced the risk of death by 38 percent in newly diagnosed patients compared to placebo. For additional information see the February, 2018 posts.

7 – Provenge (Sipuleucel-T); an immunotherapy developed by Dendreon and approved in 2011 by the FDA for treatment of asymptomatic or minimally-symptomatic, metastatic, hormone-refractory prostate cancer. It works by inducing an immune response by activated T-cells in a patient’s immune system against a protein called Prostatic Acid Phosphatase (PAP) which is produced in 95% of all prostate cancers. For a review, see http://www.provenge.com. (Discussed in June 3rd and Sept. 20th, 2011 blog posts).

8 – Xgeva (Denosumab); An injectable, monoclonal antibody approved by the FDA to prevent bone fractures and other skeletal events. In 2010, it was originally approved only in prostate cancer patients undergoing hormonal therapy whose cancers had metastasized to bone. In 2011, its approved use was expanded to include patients with no bone metastases. (Discussed in the October 8th, 2011 blog post).®prostatic hyperplasia (BPH). It works by inhibiting an enzyme called 5-alpha reductase which converts testosterone to its more potent form, dihydrotestosterone (DHT) which is ten (10) times more powerful than testosterone for driving the growth of advanced prostate cancer. (Discussed in the Feb. 25th, 2011 blog post).

9 – Xtandi® (enzalutamide, formerly MDV3100); Approved by the FDA on August 30th, 2012 and Sept. 2014 for treatment of metastatic, hormone refractory prostate cancer patients who have either failed chemotherapy such as taxotere (docetaxel) or who have never have had chemotherapy.  Xtandi disrupts tumor cells’ ability to use testosterone by blocking the cell’s testosterone receptors and prevents the production of androgens within the cell itself. It is an oral, androgen receptor antagonist and does not require co-administration of steroids such as prednisone. It was developed and is distributed by Medivation Inc. (San Francisco, CA) and Astellas Pharma Inc. (Japan). For more information, see the blog posts dated September 14th, 2012 and earlier, viz., June 9th, 2012,  Feb. 10th, 2012, Nov. 21st, 2011, May 7th, 2011 and June 19th, 2014.

10 – Xofigo (previously known as alpharadin); Approved on May 15th, 2013 by the U.S. Food and Drug Administration for use in men with treatment-resistant prostate cancer that had metastasized to bones but not to other organs. Xofigo, administered by injection, will be marketed by Bayer Healthcare Pharmaceuticals who developed the therapy jointly with Algeta, ASA, a Norwegian pharmaceutical company. The drug works by delivering radioactive alpha particles directly to prostate cancer cells that have formed tumors in bone. The radioactive alpha particles from radium-223 dichloride are relatively “heavy” and therefore do not penetrate very far in the body thus limiting the effect of the drug to about a 10-cell radius thereby limiting its toxicity. The drug binds with minerals in the bone to deliver radiation directly to the bones limiting damage to surrounding tissues. For further information, see the June 3rd, 2013 blog post or http://xofigo-us.com. Earlier information can be found in the blog posts dated Nov. 5th, 2011 and Feb. 10th, 2012.

11 – Erleada (apalutamide, formerly ARN-509). In February 2018, the U.S. Food and Drug Administration (FDA) approved a next-generation androgen receptor inhibitor, as therapy for patients with localized (non-metastatic) prostate cancer who failed to respond to hormone therapy. This makes Erleada the first FDA-approved therapy for non-metastatic, castration-resistant prostate cancer. The decision was supported by results from SPARTAN  (a Phase 3 trial showing that treatment with Erleada decreased the risk of cancer spreading (metastasis) or death by 72 percent, and increased the time it took for the cancer to metastasize by more than two years. See February 16th, 2018 post.  

In September, 2019 Erleada was also approved for treatment of men with metastatic, castration (hormone)-sensitive prostate cancer. See September 24th, 2019 blog.

12- Olaparib: On May 19th, 2020, the U.S. Food and Drug Administration (FDA) approved olaparib (Lynparza), an oral poly ADP-ribose polymerase (PARP) inhibitor, for monotherapy treatment of BRCA1/2 or ATM gene – mutated, metastatic, hormone-resistant prostate cancer. To receive this drug, men must also have specific genetic alterations that prevent their cells from repairing damage to their DNA. Olaparib blocks the activity of the PARP protein which helps cells mend specific types of damage to DNA. PARP inhibitors work in part by blocking the ability of PARP proteins to repair damaged DNA, which includes recruiting other DNA repair proteins. For more information, see the August 29th, 2020 post.

13- Rubraca (rucaparib): This oral PARP inhibitor, developed by Clovis Oncology, was approved by the FDA on May 15th, 2020. It is only approved for use in men with mutations in BRCA1 or BRCA2 and only for cancer that has progressed despite earlier treatment with both a hormone-blocking treatment as well as chemotherapy. Rubraca shrank tumors in 44% of metastatic hormone-resistant prostate cancer (mCRPC) patients with BRCA mutations included in the Phase 2 TRITON2 clinical trial. The treatment, which is already approved for ovarian cancer, also reduced PSA levels — a biomarker of prostate cancer — in 51.1% of patients. For additional information, see the March 25th, 2020 blog and the blog posted in November 8th, 2018. For more complete information, see the August 29th, 2020 post.

14- Darolutamide (ODM-201, Nubeqa). Results from a Phase 3 ARAMIS clinical trial revealed that adding the androgen receptor inhibitor darolutamide to androgen deprivation (hormone) therapy (ADT) extends by 22 months the time men with hormone-resistant prostate cancer live without metastasis and without increasing the incidence of adverse events. The treatment also extended survival, time to pain progression, time until chemotherapy was needed, and kept patients alive and progression-free for longer periods than ADT alone. It is being jointly developed by Orion and Bayer Pharmaceuticals. It is an oral, androgen receptor antagonist whose mechanism of action is similar to enzalutamide and apalutamide (above) though it differs structurally. Darolutamide does not penetrate the brain or CNS as much as others drugs which minimizes potential side effects such as seizures, strokes, fractures and falls. Darolutamide was approved by the FDA on July 30th, 2019 for use in non-metastatic, hormone-resistant prostate cancer. For more information, see this Prostate Cancer Foundation article, April 25th, 2019 blog, the July 7th, 2014 blog and the February 13th, 2017 blog.

15-Orgovyx (relugolix), an oral form of hormone therapy by Myovant Sciences, to treat adults with advanced prostate cancer. The approval on Dec. 22, 2020, granted under priority review, was based on data from the HERO Phase 3 trial (NCT03085095), in which Orgovyx significantly increased the proportion of patients with sustained reductions in testosterone levels over nearly one year, compared with standard-of-care leuprolide acetate. Treatment also lowered the risk of major cardiovascular events by more than half. For additional information, see the February 8th, 2021 post.

Therapeutic agents not yet approved for prostate cancer but under clinical development include:

1 – Ipilimumab; (also known as MDX-101 and MDX-010 and marketed as Yervoy) is a human monoclonal antibody developed by Bristol-Myers-Squibb and approved for the treatment of melanoma. It recently failed to show a response in locally advanced prostate cancer (see April 11th, 2017 blog). It is currently undergoing clinical trials in metastatic, hormone-refractory prostate cancer among other cancers. It works by activating a patient’s own immune system by causing cytotoxic T-lymphocytes to potentially combat tumor cells. (See June 3rd, 2011 blog post.)

2 – Capozatinib (XL184); Exelexis’ drug XL184 has already been approved by the FDA for the treatment of certain thyroid cancers. Phase II clinical trial results showed a decrease in metastatic bone lesions and pain in metastatic, hormone-refractory prostate cancer patients. XL184 inhibits an enzyme called tyrosine kinase which is involved in tumor cell proliferation and invasion, growth of new blood vessels (angiogenesis) and bone metastasis among other processes. Phase III trials are on-going in men who are resistant to Zytiga and Taxotere. These trials will evaluate the control of pain and effects on survival. Preliminary studies of XL184 have shown rapid resolution of pain and rapid disappearance of cancer abnormalities seen in bone scans. (See June 3rd, 2011 blog post).

3 – Orteronel (TAK-700); Clinical development has been discontinued. See July 12th, 2014 post. TAK-700 is a selective, oral, non-steroidal androgen synthesis inhibitor which results in lowering testosterone levels by a mechanism similar to that of Zytiga (abiraterone); it inhibits the enzyme CYP17A1. It is currently in Phase III clinical trials sponsored by Millenium and Takeda Pharmaceutical in metastatic, hormone-refractory prostate cancer patients irrespective of whether they have received chemotherapy with docetaxel (taxotere). (See May 7th, June 3rd, and Nov. 21st, 2011 blog posts). See also Wikipedia.

4 – Prostvac; A therapeutic pox-virus vaccine originally formulated at the National Cancer Institute (NCI) and being developed in collaboration with Bavarian-Nordic A/S. It stimulates the immune system to attack cancerous, PSA-producing cells. It is currently in Phase III clinical trials (PROSPECT, initiated in November 2011) in asymptomatic or minimally-symptomatic, hormone-resistant patients. There is considerable interest in administering Prostvac to patients in earlier stages of disease. It is available in clinical trials. (See Sept. 20th blog post and http://www.bavarian-nordic.com/pipeline/prostvac.aspx). This vaccine has not been shown to improve survival, hence it has failed this aspect of Phase 3 clinical trials.

5 – Galeterone (TOK-011); Discontinued development 8/1/2016; Phase III trials discontinued since drug did not meet its endpoints; see link. In Phase III clinical trials for hormone-resistant prostate cancers. It is being developed by Tokai Pharmaceuticals Inc.  Additional information is  now included in a blog posted on January 6th, 2013. Galeterone, an oral drug also known as TOK-011, is unique in that it is the first and only single-agent therapeutic that combines three distinct approaches to attack prostate cancer and which thereby may help to prevent resistance to ADT. Galeterone works by blocking testosterone synthesis (specifically by blocking the enzyme CYP17 lyase), blocking testosterone’s ability to bind to its androgen receptor and finally, by limiting overall androgen receptor levels in the body. Galeterone’s development and review has received a “fast-track designation” by the U.S. Food and Drug Administration.  For additional information, see the January 6th, 2013 blog and the references therein as well as Wikipedia.

6 – Custirsen (OGX-011); Failed to improve overall survival in advanced cancer patients. See Sept. 4th, 2016 blog. Custirsen is designed to block production of clusterin, a cell survival protein that is over-produced in several cancer types of cancer and in response to many cancer treatments, including hormone ablation therapy, chemotherapy and radiation therapy. Custirsen is an “antisense drug” which short-circuits the production of necessary proteins in a cell thus killing it. The technology is based on using short pieces of single-stranded RNA to bind to a cell’s messenger RNA (mRNA) which is the molecule responsible for shuttling protein-making instructions from DNA in the cell’s nucleus to the ribosome, the cell’s protein manufacturer. Custirsen is in Phase III clinical trials in combination with Jevtana and also in a separate trial (Synergy) in combination with chemotherapy in patients for hormone-resistant prostate cancer.  For further information, see the OncoGeneX website. See also the March 26th, 2012 website entries in the 2012 blog section.

7 – OGX-427: Another drug under development by OncoGeneX. OGX-427 is a second generation antisense drug which, in preclinical experiments, inhibits production of Heat Shock Protein 27 (Hsp27), a cell survival protein found at elevated levels in many human cancers. The Phase II development program for OGX-427 aims to demonstrate inhibition of Hsp27 can lead to improved prognosis and treatment outcomes for cancer patients. For further information, see the OncoGeneX website. See also the March 26th, 2012 website entries in the 2012 blog section.

8 – BIND-014: A nanoparticle delivery system for taxotere (docetaxel) currently in Phase II clinical trials in men with metastatic, treatment-resistant prostate cancer and non-small cell lung cancer. BIND-014 is being developed by BIND Therapeutics of Cambridge, MA. It is described in the December 5th, 2013 blog.

9- Tasquinimod, or TASQ (ABR-215050), is an oral experimental treatment for men with metastatic, treatment-resistant prostate cancer. Chemically, TASQ is a quinoline-3-carboxamide with three-pronged immunomodulatory (activates the body’s immune system to fight cancer), anti-angiogenic (prevents the formation of new blood vessels to feed tumor cells) and anti-metastatic (inhibiting tumor growth) activity. After completing Phase I and II clinical trials, Active Biotech and Ispen, the drug’s developers, announced successful enrollment of 1,200 patients in 250 clinics for a global, randomized, double-blind, placebo-controlled Phase III clinical trial evaluating TASQ in men with metastatic, hormone-refractory prostate cancer. For additional information, see the January 6th, 2013 blog post and the references therein.

10- Fexapotide triflutate; (NX-1207); NX-1207 is a novel drug under development by Nymox Pharmaceutical targeting patients with localized prostate cancer such as those under active surveillance. It can be injected directly into the prostate by a urologist in an office procedure that takes a few minutes, does not require any type of anesthesia or catheterization, and involves little or no pain or discomfort. It is currently in Phase 2 clinical trials. See the following link for more information.

11- Topsalysin; (PRX302); This drug being developed by Sophiris Bio. targets patients with BPH or low- to intermediate risk prostate cancer. PRX302 is a modified recombinant protein engineered to be selectively activated by an enzyme in the prostate, leading to localized cell death and tissue disruption without damaging neighboring tissue and nerves. PRX302 binds to the GPI-anchored receptors on the surface of prostate cells. Once activated by PSA, a protein produced by normal and cancerous prostate cells, PRX302 combines with other activated PRX302 molecules to form stable transmembrane pores that induce cell death. Prostate-specific activation of PRX302 by enzymatically active PSA thus limits exposure of non-prostate tissues to the drug’s activity, the company reports, contributing to the therapy’s safety. It is currently in Phase 2 trials. See the following link.

12- EPI-7386 is a new androgen receptor inhibitor, selected as Essa Pharma’s lead candidate therapy for metastatic castration (hormone)-resistant prostate cancer (mCRPC). EPI-7386 works differently from current hormonal therapies by targeting a different region of the androgen receptor: instead of preventing androgens from binding the receptor, EPI-7386 binds to the N-terminal domain needed to activate the androgen receptor signaling cascade. Through this novel mechanism, EPI-7386 is able to block the androgen receptor even in cells that acquired resistance to other androgen receptor inhibitors, like Xtandi (enzalutamide). Essa has begun Phase 1 clinical trials of EPI-7386 at 4 different doses in September 2020 (NCT04421222).

13- VERU-111 has entered the Phase 2 portion of a clinical trial testing the safety and effectiveness of its investigational therapy, VERU-111, in men with metastatic hormone-resistant prostate cancer (mCRPC) who failed to respond to a novel androgen receptor inhibitor. VERU-111 is a first-in-class oral agent that targets tubulin, a component of microtubules, disrupting these structures. Microtubules are dynamic structures that form part of the cell’s cytoskeleton, providing shape to cells and helping them move and divide. Some chemotherapies, called taxanes —including Jevtana (cabazitaxel) and docetaxel — are already approved in the U.S. to treat metastatic prostate cancer by targeting microtubules. However, these are given intravenously, and are associated with resistance and safety concerns. VERU-111 has shown significant anti-tumor activity against prostate cancers that no longer respond to androgen deprivation therapies or second-generation androgen receptor inhibitors such as Zytiga (abiraterone acetate) or Xtandi (enzalutamide) in preclinical studies.

14- CCS1477; CCS1477, is now in Phase 1 trials in men with advanced hormone-sensitive and resistant prostate cancer as a single agent and in combination with enzalutamide (Xtandi) or abiraterone (Zytiga). It works by binding itself to two cancer gene regulators, the proteins p300 and CBP, which help activate androgen receptor signalling. By blocking the activity of these two proteins, the drug can stop prostate cancer’s growth and potentially delay or prevent drug resistance. Patients in the study who had higher levels of the p300 protein lived less long before their cancer progressed and became drug resistant than those with lower levels of the protein – 10 months compared with 21 months.

15- ARV-110 is an investigational oral candidate from Arvinas that targets the androgen receptor — a receptor protein that regulates the development and growth of prostate cancer — for degradation. Such targeted protein degraders route disease-causing proteins to the proteasome- the cell’s wood chipper, which chops up the proteins into their component amino acids.  ARV-110 is in Phase 2 trials for prostate cancer and a related compound, ARV-471 for breast cancer. In Phase 1 trials, ARV-110 showed promising anti-tumor activity in heavily pretreated men with metastatic castration-resistant prostate cancer (mCRPC). The approach worked particularly well in a population with specific mutations in the androgen receptor, but it also was found to have promising efficacy in a group of patients without genetic alterations in the receptor. Arvinas, its maker, is therefore advancing the development of ARV-110 for these two indications. According to Arvinas, these interim results support the development of ARV-110 for two key mCRPC indications. One is for heavily pretreated patients with the T878 or H875 mutations, and the other is for a less heavily treated population with a normal androgen receptor. The ARDENT Phase 2 trial will include two subgroups of patients, including one that is expected to support the treatment’s accelerated approval for heavily treated patients with T878 or H875 mutations. The second group will involve less pretreated patients who received no prior chemotherapy and only one second-generation androgen receptor inhibitor, such as Zytiga or Xtandi. This group is expected to have less genetically diverse tumors, more dependent on the androgen receptor, and therefore more likely to respond to ARV-110.

16 – Lutetium-177-PSMA is a new prostate-cancer-specific treatment continuing to show promise in patients with metastatic, hormone-resistant prostate cancer. It is currently being tested in the randomized phase 3 trial called VISION, which may report results later in 2021. If the results of this trial are favorable, Lu-PSMA may become a new standard of care treatment option for mCRPC. Prostate-specific membrane antigen (PSMA) is a protein that is present at high levels on prostate cancer cells. It can already be used in PSMA PET scanning, which was FDA-approved in December 2020, and a promising next step is to use PSMA as a target to deliver radioactive therapies (such as Lu-PSMA) straight to prostate cancer cells wherever they are in the body. A phase 2 clinical trial (TheraP) compared Lu-PSMA to a standard of care option, cabazitaxel, in patients who have previously been treated with anti-androgen therapies and taxotere. Initial results from the TheraP trial showed that many more patients treated with Lu-PSMA saw their PSA drop compared to patients treated with cabazitaxel. Results continue to suggest Lu-PSMA is a promising alternative to cabazitaxel.

This list represents a work-in-progress. The reader is urged to seek the latest additional information concerning these agents by inserting their drug names on the various available search engines such as Google, Wikipedia and websites such as that of the National Cancer Institute (http://www.cancer.gov/cancertopics/types/prostate). Additional information including available clinical trials can be obtained from the company websites developing the drugs.

Positive Phase 3 clinical trial results for the drug MDV3100 in men whose prostate cancers had progressed after failing hormonal therapy and chemotherapy have recently been reported in a special edition of the Prostate Cancer Foundation Newsletter, November 7th, 2011 (see http://www.pcf.org/site).  Such positive results were observed that the trial was stopped early and the drug provided to men who had been previously receiving the placebo.  MDV3100 was found to increase the median survival time by 4.8 months and provided a 37% reduction in the risk of death when compared to placebo. Some men had more durable remissions while some did not respond. Based on these results, the drug’s developers, Medivation Inc. and Astellas Pharma Inc., plan to submit MDV3100 to the Food and Drug Administration for approval in 2012.  MDV3100 has been under clinical development in advanced prostate cancer patients who have already received chemotherapy with taxotere (docetaxel) as well as those who have not been treated with taxotere.  MDV3100 works by blocking the androgen receptor (which is the engine that drives prostate cancer progression) at three distinct points in the cell-signaling pathway.  The drug blocks testosterone (the fuel that drives the engine) from binding to the androgen receptor (the engine), impedes movement of the androgen receptor to the nucleus of prostate cancer cells (nuclear translocation) and inhibits binding to DNA. MDV3100 has been described in an earlier blog (February 18^th, 2011) on this website.

Stopping of a clinical trial and offering the drug to patients taking the placebo had occurred earlier this year with the FDA-approved drug Zytiga (abiraterone acetate). Zytiga affects prostate cancer progression by shutting off the supply of testosterone, the fuel that drives the cancer engine. Using both MDV3100 and Zytiga together seems to be a very logical idea. A Phase 3 trial is already underway in hormone-resistant (refractory) prostate cancer patients who have never received chemotherapy. The results are not yet available but the trend will be to use both drugs earlier in the history of prostate cancer patients. They could possibly be used to potentially cure patients with high-risk cancer who had not yet been treated surgically.

At the annual American Society of Clinical Oncology (ASCO) meeting in Chicago in June 2011, the Prostate Cancer Foundation September 30th newsletter reported on promising Phase III clinical trial results for radium-223 chloride (alpharadin), an agent specifically being developed for cancer patients with bone metastases. The drug works by emitting small doses of alpha particle radiation that damage the DNA of cancer cells, thereby killing them without harming healthy cells. [It should be noted that in comparison with other radioactive particles, alpha particles are quite heavy and do not penetrate surrounding tissues very far.] The data presented indicated that alpharadin significantly improves overall survival in patients with hormone-resistant prostate cancer that has metastasized to the bone. This conclusion was also cited in a report in the October 4th ZeroHour Newsletter. Thus, alpharadin may be the first drug to improve survival in men with cancer of the prostate that has spread to the bone, a worsening of the disease that occurs in 90 percent of men in the advanced stages of the disease.

Alpharadin was initially discovered by a Norwegian company Algeta ASA and was subsequently exclusively licensed to Bayer HealthCare Pharmaceuticals. On the basis of the results described above, alpharadin has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for the treatment of castration-resistant (hormone-refractory) prostate cancer in patients with bone metastases. Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious diseases and fill an unmet medical need, thereby hopefully leading to earlier drug approval and access by patients. Bayer plans to apply for regulatory approval in Europe and the U.S. by the middle of next year.