Clinical Overview of Innovative New Drug Approvals in 2017

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1 Reddy: Clinical Overview of Innovative New Drug Approvals in International Journal of Pharmaceutical Sciences and Nanotechnology Review Article Clinical Overview of Innovative New Drug Approvals in 2017 Prof. D. Samba Reddy* Professor & Editor-in-Chief, IJPSN, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas 77807, USA. Received May 10, 2018; accepted July 28, 2018 ABSTRACT The FDA has approved 46 new drugs in 2017, another record approval in two decades on a similar pace to the gangbuster year of Many of these new medicines address significant and meaningful needs, or offer additional therapeutic choices for patients worldwide. These new drugs also cover a broad range of indications including immunooncology (Imfinzi and Bavencio), Parkinson s disease (Xadago), eczema (Dupixent), psoriasis (Siliq and Tremfya), multiple sclerosis (Ocrevus), and different types of cancer (Idhifa, Aliqopa, Calquence, and Besponsa). A few important orphan drugs were approved, including in mucopolysaccharidosis type VII (Mepsevil) and Batten s Disease (Brineuria). Many of these new drugs are for rare diseases Volume 11 Issue 5 September October 2018 and sub-types of cancer, which often target very small populations, although they can cost hundreds of thousands of dollars. Yet the pharma companies saw average returns on their research and development spending fall, reflecting more competitive pressures and the growing share of new products now coming from biotech companies. Recently, the US has introduced the Right-to-Try Act, wherein patients can access experimental treatments if they are unable to participate in any clinical trial of new drugs and if they have no other options. Such policies are expected to increase the database for new experimental drugs and help accelerate drug approvals. KEYWORDS: New drugs; NCEs, Biologics, Fast-track; First-in-class; Orphan drugs; Block-buster drugs MS ID: IJPSN REDDY Introduction The American pharma industry is the leading drugmaker worldwide. United States is host to big pharma companies like Pfizer, Merck, Johnson & Johnson, GSK, Novartis, Genentech, Eli Lilly, and other companies. The current landscape of big pharma in the United States is rapidly changing in tune with the global economy (Reddy, 2015). The Hatch-Waxman Act transformed pharma business with generic drugs since Big pharma companies continue to drive the introduction of new drugs despite huge risks and regulatory uncertainties. Drug development is a lengthy and expensive process, estimated to cost $1.2 billion. Current trends in new drug approvals in the US show that the number of new drugs has decreased or almost steady during the past decade, despite steady increases in R&D investment (Scannel et al., 2012). The pipeline of new drugs under development is strong and growing, yet there is still a big shortage for blockbuster drugs with sales of over $1 billion. Drug discovery is a tedious and expensive affair, and it takes about 5 to 10 years to introduce a new drug (Reddy and Woodward, 2004; Scannel et al., 2012; Reddy, 2012; 2013; 2014; 2016; 2017). In 2017, the FDA has given a green signal to 46 novel drugs, another record approval in two decades on a similar pace to the gangbuster year of 2015 (CDER, 2018) (Table 1). This number is the highest in recent history, indicating another year of excellent innovation and productivity within the pharma and biotech industry (Mullard, 2016). New drugs are as NMEs under New Drug Applications (NDAs), or as new therapeutic biologics under Biologics License Applications (BLAs). New drugs are classified as new molecular entities (NMEs) or new chemical entities (NCEs) if the products contain active moieties that have not been approved previously by the FDA, either as a single ingredient drug or as part of a combination product. Such products represent innovation and provide important new therapies for patients. This list of 46 novel drugs includes a wide range of new drugs and biologic products. This article provides an overview of the new drugs in Number of NME Approvals Fig. 1. New drug approvals from 2005 to 2017 in the United States. Source: FDA

2 4226 Int J Pharm Sci Nanotech Vol 11; Issue 5 September October 2018 Prominent Novel Drugs of 2017 The United Staes FDA is the leading authority for drug approvals worldwide. There are many regulatory pathways or schemes for accelerated approval of novel drugs. Figure 1 shows the number of novel drugs approvals by the FDA during the past 10 years. About 30% of new drugs are biologics. About 28 novel drugs were approved annually during the past 10 years (CDER, 2018; Jarvis, 2016). The success rate of NDA approvals greatly increased within the recent years with many drug approvals. This is especially true of the year 2017, which witnessed a record approval of 46 new drugs (Table 1), all of which are notable for their promising impact and contributions to reduce the disease burden in the United States and all over the world. TABLE 1 Novel new drug approvals in 2017 (alphabetical order). Brand Name Generic name Approval Indications Aliqopa copanlisib 9/14/2017 To treat adults with relapsed follicular Alunbrig brigatinib 4/28/2017 To treat patients with anaplastic kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib Austedo deutetrabenazine 4/3/2017 For the treatment of chorea associated with Huntington s disease Bavencio avelumab 3/23/2017 To treat metastatic Merkel cell carcinoma Baxdela delafloxacin 6/19/2017 To treat patients with acute bacterial skin infections benznidazole benznidazole 8/29/2017 To treat children ages 2 to 12 years old with Chagas disease Besponsa inotuzumab 8/17/2017 To treat adults with relapsed or refractory acute lymphoblastic leukemia ozogamicin Bevyxxa betrixaban 6/23/2017 For the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness Brineura cerliponase alfa 4/27/2017 To treat a specific form of Batten disease Calquence acalabrutinib 10/31/2017 To treat adults with mantle cell Dupixent dupilumab 3/28/2017 To treat adults with moderate-to-severe eczema (atopic dermatitis) Emflaza deflazacort 2/9/2017 To treat patients age 5 years and older with Duchenne muscular dystrophy (DMD) Fasenra benralizumab 11/14/2017 For add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype Giapreza angiotensin II 12/21/2017 To increase blood pressure in adults with septic or other distributive shock Hemlibra emicizumab 11/16/2017 To prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors. Idhifa enasidenib 8/1/2017 To treat relapsed or refractory acute myeloid leukemia Press Release Drug Trials Snapshot Imfinzi durvalumab 5/1/2017 To treat patients with locally advanced or metastatic urothelial carcinoma Ingrezza valbenazine 4/11/2017 To treat adults with tardive dyskinesia Kevzara sarilumab 5/22/2017 To treat adult rheumatoid arthritis Kisqali ribociclib 3/13/2017 To treat postmenopausal women with a type of advanced breast cancer Macrilen macimorelin acetate 12/20/2017 For the diagnosis of adult growth hormone deficiency Mavyret glecaprevir and pibrentasvir 8/3/2017 To treat adults with chronic hepatitis C virus Mepsevii vestronidase alfa-vjbk 11/15/2017 To treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome. Nerlynx neratinib maleate 7/17/2017 To reduce the risk of breast cancer returning Ocrevus ocrelizumab 3/28/2017 To treat patients with relapsing and primary progressive forms of multiple sclerosis Ozempic semaglutide 12/5/2017 To improve glycemic control in adults with type 2 diabetes mellitus Parsabiv etelcalcetide 2/7/2017 To treat secondary hyperparathyroidism in adult patients with chronic kidney disease undergoing dialysis Prevymis letermovir 11/8/2017 To prevent infection after bone marrow transplant Drug Trials Snapshot Radicava edaravone 5/5/2017 To treat patients with amyotrophic lateral sclerosis (ALS) Rhopressa netarsudil 12/18/2017 To treat glaucoma or ocular hypertension Rydapt midostaurin 4/28/2017 To treat acute myeloid leukemia Siliq brodalumab 2/15/2017 To treat adults with moderate-to-severe plaque psoriasis Solosec secnidazole 9/15/2017 To treat bacterial vaginosis TABLE 1 Contd

3 Reddy: Clinical Overview of Innovative New Drug Approvals in Brand Name Generic name Approval Indications Steglatro ertugliflozin 12/19/2017 To improve glycemic control in adults with type 2 diabetes mellitus Symproic naldemedine 3/23/2017 For the treatment of opioid-induced constipation Tremfya guselkumab 7/13/2017 For the treatment of adult patients with moderate-to-severe plaque psoriasis Tymlos abaloparatide 4/28/2017 To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies Vabomere meropenem and 8/29/2017 To treat adults with complicated urinary tract infections vaborbactam Verzenio abemaciclib 9/28/2017 To treat certain advanced or metastatic breast cancers Vosevi sofosbuvir, velpatasvir and voxilaprevir 7/18/2017 To treat adults with chronic hepatitis C virus Vyzulta latanoprostene bunod ophthalmic solution 11/2/2017 To treat intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Xadago safinamide 3/21/2017 To treat Parkinson s disease Xepi ozenoxacin 12/11/2017 To treat impetigo Xermelo telotristat ethyl 2/28/2017 To treat carcinoid syndrome diarrhea Zejula niraparib 3/27/2017 For the maintenance treatment for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers Source: FDA In 2017, FDA s has approved many new drugs never before marketed in the United States, known as novel drugs. The FDA has approved new treatments for patients with rare diseases such as Batten disease, Chagas disease, and hemophilia A. The FDA has approved new cancer therapies, new antibiotics, and new therapies for patients with multiple sclerosis. Other firsts for approvals in 2017 will benefit patients affected by many medical conditions, including: Giant cell arteritis, a dangerous condition that results in inflammation of blood vessels; Cytokine release syndrome a condition related to a reaction caused by a treatment called chimeric antigen receptor T cell therapy; Chronic graft versus host disease after a bone marrow transplant; A type of blood cancer called marginal zone ; Eosinophilic granulomatosis with polyangiitis, a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body; and, Erdheim-Chester Disease, a rare cancer of the blood. Other firsts for FDA s drug therapy approvals that are not novel drug approvals include the first: Biosimilars to treat certain cancers; Immediate-release opioid product with properties intended to deter abuse; Once-monthly injectable buprenorphine product to help patients struggling with opioid addiction; Cancer treatment based on a genetic feature of the cancer rather than the location of the body where the tumor originated; Treatment to help prevent recurrence of renal cell carcinoma (kidney cancer); Complete regimen to treat HIV-1 that contains only two drugs, neither a nucleoside reverse transcriptase inhibitor, which can be detrimental to a patient s kidneys, bones, and heart; Drug in the United States with a sensor embedded in the pill that enables a patient to create an electronic record that the medication was taken; and, Short-acting follow-on insulin product to treat patients with diabetes. Therapeutic Categories of New Drugs of 2017 Cardiovascular Diseases Bevyxxa (betrixaban); prophylaxis of venous thromboembolism Dermatology Bavencio (avelumab); treatment of Merkel cell carcinoma Baxdela (delafloxacin) tablets and injection; treatment of acute bacterial skin and skin structure infections Dupixent (dupilumab); treatment of atopic dermatitis Eskata (hydrogen peroxide); treatment of seborrheic keratoses Rhofade (oxymetazoline); treatment of facial erythema associated with rosacea Siliq (brodalumab); treatment of plaque psoriasis Tremfya (guselkumab); treatment of moderate-tosevere plaque psoriasis Xepi (ozenoxacin); treatment of impetigo Endocrinology Macrilen (macimorelin); diagnosis of adult growth hormone deficiency Ozempic (semaglutide); treatment of type II diabetes Parsabiv (etelcalcetide); treatment of secondary hyperparathyroidism in adults with chronic kidney disease on hemodialysis

4 4228 Int J Pharm Sci Nanotech Vol 11; Issue 5 September October 2018 Qtern (dapagliflozin and saxagliptin); treatment of inadequately controlled type II diabetes Steglatro (ertugliflozin); treatment of type 2 diabetes mellitus Family Medicine Ozempic (semaglutide); treatment of type II diabetes Qtern (dapagliflozin and saxagliptin); treatment of inadequately controlled type II diabetes Steglatro (ertugliflozin); treatment of type 2 diabetes mellitus Trulance (plecanatide); treatment of adults with chronic idiopathic constipation Gastroenterology Symproic (naldemedine); treatment of opioid-induced constipation Trulance (plecanatide); treatment of adults with chronic idiopathic constipation Xermelo (telotristat ethyl); treatment of carcinoid syndrome diarrhea Genetic Disease Haegarda (C1 Esterase Inhibitor Subcutaneous); routine prophylaxis to prevent Hereditary Angioedema attacks neuronal ceroid lipofuscinosis type 2 Mepsevii (vestronidase alfa-vjbk) treatment of Mucopolysaccharidosis VII Hematology Aliqopa (copanlisib); treatment of follicular Besponsa (inotuzumab ozogamicin); treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia Calquence (acalabrutinib); treatment of mantle cell Endari (L-glutamine oral powder); treatment of sickle cell disease Giapreza (angiotensin II); treatment of septic shock Hemlibra (emicizumab-kxwh); prevention or reduction of bleeding episodes in patients with hemophilia A IDHIFA (enasidenib); treatment of relapsed or refractory acute myeloid leukemia with IDH2 mutation Kymriah (tisagenlecleucel); treatment of refractory B- cell precursor acute lymphoblastic leukemia Rebinyn (Coagulation Factor IX (Recombinant), GlycoPEGylated) treatment of hemophilia B Rydapt (midostaurin); treatment of FLT3 positive acute myeloid leukemia and mastocytosis Vyxeos (daunorubicin and cytarabine); treatment of newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes Yescarta (axicabtagene ciloleucel); treatment of relapsed or refractory large B-cell s Hepatology (Liver, Pancreatic, Gall Bladder) Heplisav-B [Hepatitis B Vaccine (Recombinant), Adjuvanted]; prevention of hepatitis B virus infection Mavyret (glecaprevir and pibrentasvir); treatment of chronic HCV genotype 1, 2, 3, 4, 5 or 6 Vosevi (sofosbuvir, velpatasvir, and voxilaprevir); treatment of hepatitis C Immunology Haegarda (C1 Esterase Inhibitor Subcutaneous); routine prophylaxis to prevent Hereditary Angioedema attacks Actemra (tocilizumab) injection; treatment of CAR T cell-induced severe or life-threatening cytokine release syndrome Ocrevus (ocrelizumab); treatment of multiple sclerosis Tremfya (guselkumab); treatment of moderate-tosevere plaque psoriasis Vosevi (sofosbuvir, velpatasvir, and voxilaprevir); treatment of hepatitis C Zerviate (cetirizine ophthalmic solution) treatment of ocular itching associated with allergic conjunctivitis Infections and Infectious Diseases Baxdela (delafloxacin) tablets and injection; treatment of acute bacterial skin and skin structure infections Benznidazole; treatment of Chagas disease Giapreza (angiotensin II); the treatment of septic shock Heplisav-B [Hepatitis B Vaccine (Recombinant), Adjuvanted]; prevention of hepatitis B virus infection Juluca (dolutegravir and rilpivirine); treatment of HIV-1 infection in adults KedRab [Rabies Immune Globulin (Human)]; postexposure prophylaxis of rabies infection Mavyret (glecaprevir and pibrentasvir); treatment of chronic HCV genotype 1, 2, 3, 4, 5 or 6 Prevymis (letermovir); prevention of cytomegalovirus following allogenic hematopoietic stem cell transplant Shingrix (Zoster Vaccine Recombinant, Adjuvanted); prevention of herpes zoster (shingles) Solosec (secnidazole); treatment of bacterial vaginosis Vabomere (meropenem and vaborbactam); the treatment of complicated urinary tract infections Xepi (ozenoxacin); the treatment of impetigo Internal Medicine Duzallo (lesinurad and allopurinol); treatment of hyperuricemia associated with gout Musculoskeletal neuronal ceroid lipofuscinosis type 2 Duzallo (lesinurad and allopurinol); treatment of hyperuricemia associated with gout Emflaza (deflazacort); treatment of Duchenne muscular dystrophy Kevzara (sarilumab); treatment of active rheumatoid arthritis Ocrevus (ocrelizumab); treatment of multiple sclerosis

5 Reddy: Clinical Overview of Innovative New Drug Approvals in Tymlos (abaloparatide); treatment of postmenopausal women with osteoporosis at high risk for fracture Zilretta (triamcinolone acetonide ER-release injectable suspension); treatment of osteoarthritis knee pain Nephrology Parsabiv (etelcalcetide); treatment of secondary hyperparathyroidism in adults with chronic kidney disease on hemodialysis Neurology Austedo (deutetrabenazine); treatment of chorea associated with Huntington s disease and tardive dyskinesia neuronal ceroid lipofuscinosis type Gocovri (amantadine); treatment of Parkinson's disease dyskinesia Ingrezza (valbenazine); the treatment of tardive dyskinesia Radicava (edaravone); treatment of amyotrophic lateral sclerosis Xadago (safinamide); treatment of Parkinson's disease Obstetrics/Gynecology (Women s Health) Kisqali (ribociclib); treatment of breast cancer Solosec (secnidazole); treatment of bacterial vaginosis Tymlos (abaloparatide); treatment of postmenopausal women with osteoporosis at high risk for fracture Verzenio (abemaciclib); treatment of HR+, HER2- breast cancer Zejula (niraparib); treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer Oncology Aliqopa (copanlisib); treatment of follicular Alunbrig (brigatinib); treatment of advanced ALKpositive metastatic non-small cell lung cancer Bavencio (avelumab); treatment of Merkel cell carcinoma Besponsa (inotuzumab ozogamicin); treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia Calquence (acalabrutinib); treatment of mantle cell IDHIFA (enasidenib); treatment of relapsed or refractory acute myeloid leukemia with IDH2 mutation Imfinzi (durvalumab); treatment of advanced or metastatic urothelial carcinoma and Stage III nonsmall cell lung cancer Kisqali (ribociclib); treatment of breast cancer Kymriah (tisagenlecleucel); treatment of refractory B- cell precursor acute lymphoblastic leukemia Nerlynx (neratinib); treatment of HER2 breast cancer Rydapt (midostaurin); treatment of FLT3 positive acute myeloid leukemia and mastocytosis Verzenio (abemaciclib); treatment of HR+, HER2- breast cancer Vyxeos (daunorubicin and cytarabine); treatment of newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes Xermelo (telotristat ethyl); treatment of carcinoid syndrome diarrhea Yescarta (axicabtagene ciloleucel); treatment of relapsed or refractory large B-cell s Zejula (niraparib); Tesaro; treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer Ophthalmology Luxturna (voretigene neparvovec); treatment of vision loss due to confirmed biallelic RPE65-mediated inherited retinal disease Rhopressa (netarsudil ophthalmic solution); treatment of glaucoma or ocular hypertension Vyzulta (latanoprostene bunod ophthalmic solution); reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension Zerviate (cetirizine ophthalmic solution 0.24%); treatment of ocular itching associated with allergic conjunctivitis Pediatrics/Neonatology neuronal ceroid lipofuscinosis type 2 Emflaza (deflazacort); treatment of Duchenne muscular dystrophy Rebinyn (Coagulation Factor IX (Recombinant), GlycoPEGylated); treatment of hemophilia B Pulmonary-Respiratory Diseases Imfinzi (durvalumab); treatment of advanced or metastatic urothelial carcinoma and Stage III nonsmall cell lung cancer Rheumatology Duzallo (lesinurad and allopurinol); treatment of hyperuricemia associated with gout Kevzara (sarilumab); treatment of active rheumatoid arthritis Zilretta (triamcinolone acetonide ER injectable suspension); treatment of osteoarthritis knee pain Urology Imfinzi (durvalumab); treatment of advanced or metastatic urothelial carcinoma and Stage III nonsmall cell lung cancer Vabomere (meropenem and vaborbactam); treatment of complicated urinary tract infections Vaccines Shingrix (Zoster Vaccine Recombinant, Adjuvanted; prevention of herpes zoster (shingles) Conclusions Novel drugs often represent innovative therapies for advancing patient care. In 2017, 46 new drugs were approved by the FDA. This is a record approval when compared to any year during the past decade (except 2015). Such approval trends shows an extraordinary progress in new drugs for a variety of diseases. The FDA

6 4230 Int J Pharm Sci Nanotech Vol 11; Issue 5 September October 2018 approved many new drugs to treat various forms of cancer and rare diseases such as Batten disease, Chagas disease, and hemophilia new cancer therapies, new antibiotics, and new therapies for patients with multiple sclerosis, Parkinson s disease, tardive dyskinesia, Duchenne muscular dystrophy, and amyotrophic lateral sclerosis. The path from NME discovery to product commercialization is fraught with numerous obstacles. Big pharma companies have been trying to escape the patent cliff and persuade investors to focus on their product pipelines. Biologics and orphan drugs are contributing in a big way to drug pipelines of top companies. Despite such a historic success rate with drug approvals, there is a continued productivity crisis in R&D due to a steady cost escalation for drug discovery and development. Under the FDA s Expanded Access Program, patients can take experimental drugs that have not yet been approved. In 2018, President Trump signed the Right-to- Try Act into law. This new law removes FDA involvement when patients seek experimental medications. Under this law, patients can access experimental drugs if they are unable to participate in clinical trials of investigational drugs and if they have no other options. Currently there is another procedure known as the FDA s Expanded Access Program, where patients can take experimental drugs that have not yet been approved; however, the FDA must sanction their use. Whereas the Right-to-Try benefits patients if a new drug shows promising outcome in early clinical trials, but not yet been approved. This Act enables patients to obtain investigational drugs without participating in clinical trials and without any approvals from the FDA. Under both programs, pharma companies may choose to provide new drug for patients. A market analysis estimates that the U.S. pharma market is forecasted to reach $549 billion by Pharma market growth will be driven by key factors such as increasing health care expenditure, aging population, rising prevalence of chronic lifestyle diseases such as diabetes and obesity, universal and easy access to reimbursement for medicines, and the 2010 Patient Protection and Affordable Care Act (PPACA). The PPACA and its amendment, the Health Care and Education Reconciliation Act, continue to have a substantial impact on the American pharma industry. As the PPACA mandates health insurance coverage for all Americans, the U.S. has witnessed an increase in the use of prescription drugs among individuals who are newly insured or have shifted to insurance plans that offer premium and cost-sharing subsidies. References CDER (2018). Advancing health through innovation: 2017 new drug therapy approvals. CDER, FDA Brochure, January 2018, Jarvis LM (2016). The Year in New Drugs. Chemical & Engineering News 94(5): Mullard A (2016) FDA drug approvals. Nature Reviews Drug Discovery 15: Reddy DS (2012). Novel new drug approvals in 2011: A succinct analysis of drug discovery trends in the United States. Int J Pharm Sci Nanotech 5(2): Reddy DS (2013). New drugs of 2012: A concise overview of the NMEs and trends for innovative brand market in the United States. Int J Pharm Sci Nanotech 6(2): Reddy DS (2014). An overview of novel drugs and new chemical entities in Int J Pharm Sci Nantotech 7(3): Reddy DS (2016). Novel new drugs of 2015: An extraordinary growth of innovative pharmaceuticals. Int J Pharm Sci Nantotech 9(4): Reddy DS (2017). New drugs and biologics of 2016: A boom for neurodrugs in the pipeline. Int J Pharm Sci Nantotech 10(5): Reddy DS and Woodward R (2004). Ganaxolone: A perspective overview. Drugs Future 29: Reddy SM and Reddy DS (2015). The novel drugs of 2014: Record approvals for niche markets. Int J Pharm Sci Nantotech 8(3): Scannell JW, Blanckley A, Helen Boldon H, and Warrington B (2012). Diagnosing the decline in pharmaceutical R&D efficiency. Nature Rev Drug Discovery 11: Address correspondence to: Prof. D. Samba Reddy, Professor and NIH CounterACT Investigator, Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, 8447 State Highway 47, MREB Building 2008, Bryan, Texas 77807, USA. reddy@medicine.tamhsc.edu