Defense & National Security Practice

Newsletter Fall 2018 - Note from the CEO




Dear Friends of Kinexum, 


Welcome to the Fall 2018 Kinexum Newsletter!   


Featured here are four Kinexum experts: (i) Brian Harvey, M.D., Ph.D., former director of FDA's Gastroenterology Division and former US Regulatory Vice President for Pfizer and for Sanofi, discusses the hot topic of clinical development issues in nonalcoholic steatohepatitis (NASH); (ii) Grant Williams, M.D., former Deputy Director of the FDA Oncology Division, reflects on considerations regarding accelerated approval of oncology drug combinations; (iii) Michael Sharp, Ph.D., expert in medical device regulatory strategy, explains 510(k) clearances for medical devices; and (iv) Dean Calcagni, M.D., Head of Kinexum's Defense and National Security Practice, outlines the numerous federal grant and funding opportunities beyond the NIH. 


Please mark your calendars for the next Kinexum public webcast on Friday, October 26, 2017, from 11 a.m. to noon, EST, by Nir Barzilai, M.D., Director of the Institute for Aging Research at the Albert Einstein College of Medicine, and Steve Kritchevsky, M.D., of Wake Forest, who are co-PI's of the groundbreaking Targeting Aging with MEtformin (TAME) clinical trial that will examine the effect of metformin on various markers of aging and its potential to delay multiple diseases of aging (a primer for which can be found here).


Zan and other Kinexum consultants will be in attendance at the upcoming European Association for the Study of Diabetes annual meeting in Berlin from October 1-5, 2018 and would be very pleased to meet with anyone to discuss any help we may be able to provide regarding metabolic product strategy and development issues.  


Also, please email me any feedback on my Forbes blog article, "AI in Startups."


Wishing you a productive, healthy and rewarding fall season!

Newsletter Winter 2020 - James Carroll_Why Photobiomodulation Might be the Answer to the Opioid Crisis

Why Photobiomodulation Might be the Answer to the Opioid Crisis (cont.)

What is photobiomodulation (PBM), and how does it help solve the opioid crisis?

Disclosure: James Carroll is Founder & CEO of THOR Photomedicine Ltd, as well as Co-founder of and Investor in Lumithera, Inc.

The opioid crisis
You probably do not need much reminding about America’s opioid crisis; the numbers are huge. CDC figures state that there are 100 million adults in the United States (US) affected by chronic pain, and over $600 billion a year are spent on health care costs related to pain and lost productivity. There were over 49,000 deaths associated with opioids in 2017—19,000 of which came from prescribed opioids.

According to the Assistant Secretary for Health, Admiral Brett Giroir, “you cannot solve the opioid crisis without solving the pain crisis” [1].

PBM is something you have seen on Star Trek. 
On Star Trek, when somebody was injured, the doctor would aim a low-intensity laser beam at the injury, and the wounds would heal instantly! That is photobiomodulation (PBM). The effects are not as fast as shown on TV, but the idea is the same: light is shone on people, and they get better more quickly. 
PBM is a non-thermal light therapy that reduces the underlying causes of pain: trauma, inflammation, degenerative joints, and neuropathies. PBM utilizes low-intensity lasers and LED devices in the red and near-infrared spectrum (600–1000 nm) to stimulate mitochondrial function, which leads to increased ATP production, reduced oxidative stress (which leads to less inflammation), and better tissue regeneration.
There are no known side effects, though occasionally there are some mild short-term treatment reactions. It is cleared by FDA, Health Canada, Europe, and Australia for muscle and joint pain, and it is widely used in the US.

Evidence for PBM
There are over 6,400 published academic papers indicating that PBM, when correctly delivered, reduces musculoskeletal pain (back pain, neck pain, degenerative joint diseases, and tendinopathies), neuropathic pain (shingles, postherpetic neuralgia, trigeminal neuralgia, and diabetic peripheral neuropathies), dental pain (post-tooth extraction, burning mouth syndrome, and other neuropathies), and other postsurgical pain (hip replacement, total knee replacement, and open heart surgery).
There are over 700 randomized controlled clinical trials (RCTs) on PBM. Additionally, there are more than 4,000 laboratory studies looking at the mechanism of action and dose-response. It appears in more than 200 systematic reviews. In 2018, 443 papers on PBM were published.
PBM was previously known as Low-Level Laser Therapy (LLLT), but now the National Library of Medicine has adopted “photobiomodulation” as the official medical subject heading (MeSH) [2].
PBM is a recommended treatment for oral mucositis (a side effect of radiotherapy for cancer) by the National Institute Health and Care Excellence (NICE) in the UK and the Multinational Association for Supportive Care in Cancer (MASCC) [3, 4].
The American College of Physicians Guidelines for Noninvasive Treatments for Acute, Subacute & Chronic Low Back Pain includes PBM as a “strong recommendation” [5].
The British Journal of Sports Medicine published a systematic review of the effectiveness of conservative and surgical interventions for frozen shoulder and found “strong evidence” for the effectiveness of PBM in the short term [6].
The Lancet published a systematic review and meta-analysis of RCTs for neck pain. It concluded that PBM is "non-invasive, painless, and can be easily administered in primary-care settings." It also stated, "The incidence of adverse effects is low and similar to that of placebo, with no reports of serious events, and the results contrasted with those for drug therapies for which the effect ends rapidly when drug use is discontinued" [7].
The British Medical Journal (BMJ) published a systematic review and meta-analysis on the efficacy of PBM on pain and disability in knee osteoarthritis, concluding that "the positive effect from PBM seems to last longer than those of widely recommended painkiller drugs. It is important to note that no adverse events were reported by any of the trial authors, and the dropout rate was minor, indicating that PBM is harmless" [8].
The British Medical Journal (BMJ) published another systematic review with meta-analysis, this time on the efficacy of PBM for chronic non-specific low back pain. The meta-analysis suggests that PBM, when used by itself or in combination with other modalities, may achieve a useful reduction in pain for up to 3 months in chronic non-specific low back pain with few adverse effects [9].
How does PBM work?

Primary effect (absorption)
There is a consensus that cytochrome c oxidase (CcO) in mitochondria is the primary photo-acceptor of PBM light, with a cascade of molecular events following such absorption [10–12]. There are some additional mechanisms, but the CcO pathway explains most of the benefits seen from PBM.
Secondary effects (mitochondrial)
Following light absorption by CcO, there is increased oxygen consumption by mitochondria, with a corresponding increase in ATP production, a burst of reactive oxygen species (ROS) and nitric oxide (NO), followed by a reduction in ROS (i.e., superoxide, hydrogen peroxide) [13–15].
Tertiary effect (intracellular)
The changes in ROS, reduced oxidative stress (and subsequent increase in ATP followed by more cAMP), resets NF-kb (reducing inflammation, cell death, and gene expression associated with degenerative diseases) and up-regulates gene transcription factor AP-1, which is associated with tissue repair, cell survival, increased activation of enzymes and secretion of growth factors and secondary messengers that signal to other cells [16–18].
Quaternary effects (extracellular)
The growth factors and secondary messengers serve as signal transduction messengers to neighboring cells, leading to indirect, distant, systemic responses in tissues/organs that have not absorbed photons via chemotactic, neural, lymphatic, and humoral effects [19–21].
Dose response
PBM dosage is a combination of both light intensity and treatment time. If there is insufficient intensity or insufficient treatment time, there are no benefits. On the other hand, if there is too much intensity or too much treatment time, the benefits disappear. Typically, treatment time ranges from 20 seconds to 20 minutes, and the ideal intensity is in the range of 10 – 100 mW/cmfor superficial pathologies less than 1 cm below the skin surface. There are exceptions and anomalies in the literature, however, that need some expert interpretation [22, 23].
Physiological effects
This cascade of events leads to improved speed and quality of tissue repair (skin, muscle, tendon, ligament, cartilage, bone, sensory nerves, motor nerves, and central nervous system), reduced inflammation and edema, improved function, and anti-aging effects [24–26].
Two papers I would like to highlight:
1. The effect of PBM on the duration and severity of postoperative pain: a double-blind trial
Moore KC, Hira N, Broome IJ, Cruikshank JA
Departments of Anaesthesia and General Surgery, The Royal Oldham Hospital, Oldham, UK; The Royal Hallamshire Hospital, Sheffield, UK; General Practitioner, Pennymeadow Clinic, Ashton-under-Lyne, UK
This trial was designed to test the hypothesis that LLLT reduces the extent and duration of postoperative pain. Twenty consecutive patients for elective cholecystectomy were randomly allocated for either LLLT or as controls. The trial was double blinded. Patients for LLLT received 6–8 minutes of treatment (GaAlAs: 830 nm: 60 mW CW: CM) to the wound area immediately following skin closure prior to emergence from general anesthesia (GA). All patients were prescribed on-demand postoperative analgesia (intramuscular [IM] or oral, depending on pain severity). Recordings of pain scores (0-10) and analgesic requirements were noted by an independent assessor. There was a significant difference in the number of doses of narcotic analgesic (IM) required between the two groups (controls n=5.5; LLLT n=2.5). No patient in the LLLT group required IM analgesia after 24 hours. Similarly, the requirement for oral analgesia was reduced in the LLLT group (controls n=9; LLLT n=4). Control patients assessed their overall pain as moderate to severe compared with mild to moderate in the LLLT group. The results justify further evaluation on a larger trial population [27].


Effect of PBM on severity of postoperative pain
2. Double blind crossover trial of low level laser therapy in the treatment of post herpetic neuralgia
Moore KC, Hira N, Parswanath K, Copparam J, Ohshiro T
Departments of Anaesthesia and General Surgery, The Royal Oldham Hospital, Oldham, UK
Postherpetic neuralgia can be an extremely painful condition that—in many cases—proves resistant to all the accepted forms of treatment. It is frequently most severe in the elderly and may persist for years with no predictable course. This trial was designed as a double-blinded assessment of the efficacy of LLLT in the relief of the pain of postherpetic neuralgia, with patients acting as their own controls. Admission to the trial was limited to patients with established postherpetic neuralgia of at least six months’ duration and who had shown little or no response to conventional methods of treatment. Measurements of pain intensity and distribution were noted over a period of eight treatments in two groups of patients each, of which received four consecutive laser treatments. The results demonstrated a significant reduction in the pain intensity and distribution following a course of PBM [28].

Effect of PBM in posthepatic neuralgia

Psychological effects
Many individuals who develop substance use disorders (SUD) are also diagnosed with mental disorders. Multiple national population surveys have found that about half of those who experience a mental illness during their lives will also experience a substance use disorder [29].
PBM has positive effects on the brain, including reduced depression and anxiety, improved cognitive function in healthy adults, and on various forms of dementia. In 2018, Cassano conducted a double-blind RCT on patients with major depressive disorder. He demonstrated an "anti-depressive effect with medium to large effect size and significant findings" [30]. In 2016, Disner showed in an RCT that PBM enhanced the effects of attention bias modification treatment of depression [31]. In 2009, Schiffer treated 10 patients with major depression, including 9 with anxiety, 7 with a past history of substance abuse (6 with OUD, and 1 with an alcohol abuse history), and 3 with post-traumatic stress disorder. These patients experienced highly significant reductions in both depression and anxiety scores following treatment, with the greatest reductions occurring at two weeks [32].

PBM Technology

PBM addresses three components that are typically present in OUD:
  1. PBM reduces pain (diminishing the initial use of opioids). 
  2. PBM is regenerative (helping heal the underlying cause of the pain). 
  3. PBM decreases a psychological component of OUD (depression and anxiety).
It can be used exclusively or as an adjunct to existing treatments. 
Given the evidence for its efficacy, we believe PBM should be part of the solution to the opioid crisis.
[1] Giroir BP. You cant solve the opioid crisis without solving the pain crisis”. Arthritis Foundation, 2019.
[2] Anders JJ, Lanzafame RJ, Arany PR. Low-level light/laser therapy versus photobiomodulation therapy. Photomed Laser Surg, 2015. 33(4): 183-4.
[3] Low-level laser therapy for preventing or treating oral mucositis caused by radiotherapy or chemotherapy. National Institute Health and Care Excellence (NICE), 2018.
[4] Zadik Y, et al. Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer, 2019. 27(10): 3969-83.
[5] Qaseem A, et al. Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med, 2017. 166(7): 514-30.
[6] Favejee MM, Huisstede BM, Koes BW. Frozen shoulder: the effectiveness of conservative and surgical interventions–systematic review. British Journal of Sports Medicine, 2011. 45(1): 49-56.
[7] Chow RT, et al. Efficacy of low-level laser therapy in the management of neck pain: a systematic review and meta-analysis of randomised placebo or active-treatment controlled trials. Lancet, 2009. 374(9705): 1897-908.
[8] Stausholm MB, et al. Efficacy of low-level laser therapy on pain and disability in knee osteoarthritis: systematic review and meta-analysis of randomised placebo-controlled trials. BMJ Open, 2019. 9(10): e031142.
[9] Glazov G, Yelland M, Emery J. Low-level laser therapy for chronic non-specific low back pain: a meta-analysis of randomised controlled trials. Acupunct Med, 2016. 34(5): 328-41.
[10] Karu T. Primary and secondary mechanisms of action of visible to near-IR radiation on cells. J Photochem Photobiol B, 1999. 49(1): 1-17.
[11] Lane N. Cell biology: power games. Nature, 2006. 443(7114): 901-3.
[12] Hamblin MR. Mechanisms and applications of the anti-inflammatory effects of photobiomodulation. AIMS Biophys, 2017. 4(3): 337-61.
[13] Agrawal T, et al. Pre-conditioning with low-level laser (light) therapy: light before the storm. Dose Response, 2014. 12(4): 619-49.
[14] Kim B, et al. Remote tissue conditioning - An emerging approach for inducing body-wide protection against diseases of ageing. Ageing Res Rev, 2017. 37: 69-78.
[15] Mitrofanis J and Jeffery G. Does photobiomodulation influence ageing? Aging (Albany NY), 2018. 10(9): 2224-5.
[16] Gao X and Xing D. Molecular mechanisms of cell proliferation induced by low power laser irradiation. J Biomed Sci, 2009. 16: 4.
[17] Peplow PV and Chatterjee MP. A review of the influence of growth factors and cytokines in in vitro human keratinocyte migration. Cytokine, 2013. 62(1): 1-21.
[18] de Farias Gabriel A, et al. Photobiomodulation therapy modulates epigenetic events and NF-kappaB expression in oral epithelial wound healing. Lasers Med Sci, 2019. 34(7): 1465-72.
[19] Hopkins JT, et al. Low-Level Laser Therapy Facilitates Superficial Wound Healing in Humans: A Triple-Blind, Sham-Controlled Study. J Athl Train, 2004. 39(3): 223-9.
[20] El Massri N, et al. Photobiomodulation reduces gliosis in the basal ganglia of aged mice. Neurobiol Aging, 2018. 66: 131-7.
[21] Wanitphakdeedecha R, et al. Local and systemic effects of low-level light therapy with light-emitting diodes to improve erythema after fractional ablative skin resurfacing: a controlled study. Lasers Med Sci, 2019. 34(2):  343-51.
[22] Huang YY, et al. Biphasic dose response in low level light therapy. Dose Response, 2009. 7(4): 358-83.
[23] Chung H, et al. The nuts and bolts of low-level laser (light) therapy. Ann Biomed Eng, 2012. 40(2): 516-33.
[24] Stergioulas A. Low-level laser treatment can reduce edema in second degree ankle sprains. J Clin Laser Med Surg, 2004. 22(2): 125-8.
[25] Cotler HB, et al. The Use of Low Level Laser Therapy (LLLT) For Musculoskeletal Pain. MOJ Orthop Rheumatol, 2015. 2(5): pii: 00068.
[26] Gopal Nambi S, et al. Radiological and biochemical effects (CTX-II, MMP-3, 8, and 13) of low-level laser therapy (LLLT) in chronic osteoarthritis in Al-Kharj, Saudi Arabia. Lasers Med Sci, 2017. 32(2): 297-303.
[27] Moore KC, et al. The Effect of Infrared Laser Irradiation (LLLI) on the Duration and Severity of Postoperative Pain: A Double Blind Trial. Laser Therapy, 1992. 4: 145-9.
[28] Moore KC, et al. A Double Blind Crossover Trial or Low Level Laser Therapy in the treatment of Post Herpetic Neuralgia. Laser Ther, 1988. Pilot Issue: 7-10.
[29] NIH. The Connection Between Substance Use Disorders and Mental Illness. National Institute on Drug Abuse, 2018.
[30] Cassano P, et al. Transcranial Photobiomodulation for the Treatment of Major Depressive Disorder. The ELATED-2 Pilot Trial. Photomed Laser Surg, 2018. 36(12): 634-46.
[31] Disner SG, Beevers CG, and Gonzalez-Lima F. Transcranial Laser Stimulation as Neuroenhancement for Attention Bias Modification in Adults with Elevated Depression Symptoms. Brain Stimul, 2016. 9(5): 780-7.
[32] Schiffer F, et al. Psychological benefits 2 and 4 weeks after a single treatment with near infrared light to the forehead: a pilot study of 10 patients with major depression and anxiety. Behav Brain Funct, 2009. 5: 46.


Alan Fisher, DrPH

Areas of Expertise:  Biostatistics, Epidemiology, Design and Analysis of Clinical Trials, Outcomes Research. 

Alan Fisher has over 40 years of experience as a Biostatistician focusing primarily on the development and submission of new drugs and biologics.  He has presented and defended the study designs and clinical results of these products to regulatory authorities in the United States, Europe and Canada.  He has also served as an expert witness for legal depositions, participated in due diligence evaluations, analyzed outcomes research (real world evidence) data, and has been a member of several Data Monitoring Committees.

Alan has statistical expertise in the areas of categorical data, analysis of variance and survival analysis.  In addition he has been involved in many successful NDA and BLA submissions to the FDA and is familiar with the current CDISC requirements.  He is also knowledgeable with adaptive designs and sequential analysis.

Alan began his career as a biostatistician at Sandoz with a primary focus on the development and submission of pindolol (Visken®) for the treatment of angina, hypertension and arrhythmia and temazepam (Restoril®).  He then joined Hoechst-Roussel and was lead statistician for cefotaxime (Claforan®), a cephalosporin antibiotic, and  pentoxifylline (Trental®), a hemorheologic  agent for intermittent claudication.  He then joined Knoll Pharmaceuticals and led the statistical analyses and subsequent submission of propafenone (Rhythmol®), an anti-arrhythmic drug.

With the opportunity to take on an increase in level of responsibility, Alan then joined Enzon as Director of Biostatistics and was responsible for the biostatistics, statistical programming and data managements functions.  Under his direction, peg-l-asparaginase (Oncaspar®), for acute lymphoblastic leukemia, and pegadenase (Adagen®), for SCID, were approved by the FDA.

Alan then joined Johnson & Johnson as the Director of Biostatistics at their Immunobiology Research Institute to work on thymopentin for reduction in the risk of progression to AIDS in HIV+ subjects. He then joined the J&J Pharmaceutical Research Institute as a Director of Biostatistics and was also the Clinical Development Team Leader for Women’s Health Products.  In this capacity he led a successful submission of Ortho Tricycle Lo®, an oral contraceptive, and the successful simultaneous submission to the FDA and the EU of Ortho EVRA®, a transdermal contraceptive.  Alan then became Director of Biostatistics for Medical Affairs at Ortho-McNeil and was involved in the analysis of Phase IV studies, line extension submissions and outcomes research (real world evidence) studies.

In 2010 Alan started consulting for both biopharmaceutical companies and non-profit organizations.  This included the role of sole statistician for the successful submission of two products sponsored by BARDA (Biomedical Advanced Research and Development Authority), obiltoximab (Anthim®) for anthrax and tecovirimat (Tpoxx®) for smallpox.  Alan also provided statistical consultation for two contraceptives developed by the Population Council.  In this capacity he met with the Indian Council for Medical Research to defend the study design for one of their products. 

Alan received his BS from Cornell University with a major in Biometry, his MS in Statistics from North Carolina State University, and a DrPH with a concentration in Biostatistics and Epidemiology from the Columbia University School of Public Health.




A list of Kinexum Newsletters and Featured Articles can be found at the pages below:


From Our Desks








Ramachandra (Ram) G. Naik, M.D.


Ramachandra G. Naik, MD


Ramachandra (Ram) G. Naik, MD, brings three decades of global institutional experience in patient care and clinical research, in both academic- and private-practice settings, and in drug and device development and medical affairs in the biopharmaceutical industry, with demonstrated clinical, strategic business, and executive leadership skills. He is currently a Professor of Medicine in the Division of Endocrinology, Diabetes, and Metabolism and an Assistant Dean at SUNY Upstate Medical University, Syracuse, NY, and is actively engaged in patient care, clinical research, and administrative activities.


Dr. Naik spent more than a decade of his professional career in private practice in Mumbai, India, as a Senior Consultant Endocrinologist at Bombay Hospital. He relocated to the United States in 2007 to join as an Assistant Professor of Medicine and Pediatrics at Barbara Davis Center for Childhood Diabetes at the University of Colorado Denver, where he was involved in patient care and clinical research activities in T1D; he was an investigator in several phase 2/3 clinical trials in the areas of immune interventions in T1D, insulin pumps, continuous glucose monitoring, and newer devices of insulin administration.


Dr. Naik transitioned into biopharmaceutical industry in 2009, and since then, has handled roles of progressively increasing responsibilities spanning all phases of clinical development and device development. Initially, as a Director in Global Cardiovascular Metabolism Franchise at Novartis Pharmaceuticals Corporation, he provided clinical leadership to late-stage development programs in diabetes and lipid disorders, was involved in business development and licensing activities, and worked closely with the translational medicine team on early development projects. He drove the initiative of establishing the Novartis “Metabolism Center of Excellence” in Hyderabad, India. Later, as a Therapeutic Area Clinical Director at Merck Research Laboratories, Dr. Naik provided strategic clinical leadership to multiple, global development programs from proof-of-concept through phase 3 registrational studies in diabetes and reproductive endocrinology. He was a core member of the Joint Development Committees of the co-development programs involving external partners (Pfizer and Samsung Bioepis). Subsequently, Dr. Naik worked at Johnson & Johnson Diabetes Care Companiesas the Senior Medical Director of Worldwide Clinical Affairs,with a focus on businesses across three distinct J&J companies providing direct leadership to insulin delivery platform (hybrid closed-loop insulin delivery program and patch insulin delivery system). In addition to providing strategic leadership to regulatory clinical studies for class II and class III devices, he designed and executed real world evidence generation studies, and provided clinical leadership for payer interactions, including value-based contracting, clinical support to digital platform, and franchise medical affairs leadership in the Asia-Pacific region. While pursuing his industry career, Dr. Naik held an academic appointment as an Adjunct Associate Professor at the University of Pennsylvania, and continued to maintain limited patient care activites.


Dr. Naik has been an active member of several professional societies, including the ADA and the Endocrine Society. He has served on the Research Grant Review Committee of the ADA. He was a recipient of 2014 Global Corporate Award in “Healthcare and Global Impact.” Dr. Naik has published in the area of autoimmune diabetes, has authored chapters in international textbooks on diabetes (including “Ellenberg & Rifkin's Diabetes Mellitus,” 6th ed., and “Therapy for Diabetes Mellitus and Related Disorders,” 5th ed., American Diabetes Association), and has given invited talks at national and international meetings. He was on the Advisory Boards of several pharmaceutical companies in India and the US prior to joining the biopharmaceutical industry.


Dr. Naik completed his post-doctoral training in endocrinology, initially, at All India Institute of Medical Sciences, New Delhi, India, and later, at the University of Washington, Seattle, WA. He was a receipient of the Juvenile Diabetes Research Foundation Postdoctoral Fellowship Award at the University of Washington. Later, Dr. Naik also pursued an executive business education from Kellogg School of Management, Northwestern University, Evanston, IL.