January 2025 - Clinical Notes
By:
Karen Cunningham January, 28 2025
Clinical Notes – January 2025
Using the Immune System to Destroy Cancer Cells
Immunotherapy is a type of cancer treatment unlike traditional chemotherapy in that it does not target the cancer itself but instead trains the immune system how to search for and destroy cancer cells. Their mechanism of action is to block checkpoint proteins such as CTLA-4, PD-L1 and PD-1 on the surface of T cells. Normally these proteins prevent T cells (a type of lymphocyte or white blood cell) from attacking healthy cells but treatment with checkpoint inhibitors unleashes the T cells to eliminate cancer cells more effectively.
The first generation of immune checkpoint inhibitors were designed to assist the immune system in recognizing and subsequently causing the destruction of cancer cells. They are considered the pillars of cancer treatment and have been in use since 2011 when Ipilumumab or Yervoy, a CTLA-4 inhibitor was approved to treat advanced melanoma. Next came the approval of Nivolumab or Opdivo, then Pembrolizumab or Keytruda both in 2014. These class of drugs are a type of immunotherapy that function by blocking checkpoint proteins from binding with their partner proteins, preventing cancer cells from sending the “off” signal to T cells enabling them to attack and kill cancer, and by initiating an immune system attack by helping to locate and attack cancer cells.
Now a new generation of immunotherapies called bispecific antibodies which target a combination of the proteins VEGF (vascular endothelial growth factor) and either PD-1 or PD-L1 proteins are being studied and may become the next generation checkpoint modulator. Interest in these drugs was piqued by a presentation in September 2024 by Summit Therapeutics of clinical data that showed its PD-1 and VEGF bispecific outperformed Keytruda in a phase 3 clinical trial for advanced lung cancer patients. In December 2024, BioNTech presented early phase data in their PD-L1 and VEGF bispecific to treat breast cancer, stating in a press release that this bispecific antibody will make up one “pillar” of the company’s oncology focus in addition to mRNA-based cancer vaccines. The data suggests that the combination of PD-1 or PD-L1 with VEGF may have important safety and efficacy profiles for cancer patients. It appears that there may be something special about this drug combination that could result in more effective results that are less toxic to the patient than by blocking PD-1 or PD-L1 and VEGF with administration of two different antibodies simultaneously. Currently it is not exactly clear what is this unique biology although scientists have some ideas regarding why this treatment looks so promising.
It is important to know how PD-1 and VEGF work to understand the hypotheses. PD-1 is a protein usually found on immune cells that binds naturally to the PD-L1 protein found in other cell types in the body. When the two proteins connect, PD-2 signals the immune cell to stand down as a way to protect the body’s own cells from being killed by the immune system. Some cancer cells also express PD-L1 and use this protein to shield themselves from immune detection. PD-1 or PD-L1 blocking antibodies stop cancer cells from doing this allowing immune cells to recognize and kill the tumor.
VEGF is also a protein that cancer cells commonly express. This protein is typically part of the wound healing process and the growth of new blood vessels known as angiogenesis. Cancer cells can take on this function to generate blood vessels that bring nutrients to the tumor that are needed for growth. VEGF can also be immune suppressive which helps malignant cells avoid death. Drugs that block VEGF help starve the tumor and make it more vulnerable to other therapies including chemotherapy or immunotherapy. These drugs are used to treat several types of cancer including but not limited to ovarian, colorectal and lung cancer. The combination of an anti-VEGF plus anti-PD-1 or PD-L1 drug is approved treatment for some cancers but often results in toxicity. When VEGF is blocked, it is being blocked throughout the entire body so the end result can be wound healing issues, nose bleeds or more severe toxicity causing hemorrhage or gastrointestinal perforations. Theoretically, when VEGF and PD-1 or PDL-1 are combined on a single molecule, it could change the distribution of the drug throughout the body by localization to tumors and lymph nodes so that the concentration is much higher in the tumor microenvironment and lymph nodes but less concentrated throughout the body. This may explain why researchers are not only seeing less toxicity from these drugs in clinical trials but they are also showing some dramatic signs of efficacy.
Bispecific immunotherapy will continue to be evaluated in clinical trials for at least a few years longer but if early results are any indication of the success of this therapy, the oncology community will have a new powerful cancer treatment option that is less toxic with improved efficacy.
German Research Team May Have Found the Cure for Systemic Lupus Erythematosus
Systemic lupus erythematosus or SLE is a life-threatening chronic disease characterized by adaptive immune system activation, formation of double-stranded DNA autoantibodies and organ inflammation. It is estimated that more than 200,000 people in the US have SLE, with women and certain racial and ethnic groups being more likely to develop this condition. SLE can affect many parts of the body including joints, skin, kidneys, blood cells, brain, heart & lungs. Symptoms can present throughout the body depending on which organs or systems are affected. These symptoms typically occur periodically and are referred to as flare ups which can be severe enough to affect a person’s daily routine. Patients may have periods of remission when they experience mild or no symptoms at all but then symptoms return. Symptom development is usually slow & one or two signs might be evident at first but then more signs or different symptoms may develop later on. The most common symptoms are joint pain, muscle pain, chest pain upon deep inspiration, headaches, fatigue, fever, hair loss, shortness of breath, swollen glands, swelling in arms/legs/face, confusion and blood clots. Lupus can also cause other chronic conditions such as photosensitivity, dry eye, depression, seizures, anemia, Raynaud’s syndrome, osteoporosis, heart disease and kidney disease.
A German research team led by physician-scientist Georg Schett was experimenting with utilizing CAR-T therapy to treat autoimmune disease. Car-T therapy involves engineering a patient’s own T cells to recognize and destroy disease causing cells. With cancer therapy, the target is malignant cells but with lupus, the target was a different type of immune cell that goes awry and signals the body to attack it’s own cells.
In 2021, a twenty year old woman diagnosed with severe lupus and experiencing organ failure underwent CAR-T therapy and subsequently achieved remission. Despite concern over potentially dangerous side effects of CAR-T, the patient felt it was her last option. Three years have passed and she has no signs of lupus. More than three dozen other patients diagnosed with lupus and now other autoimmune disease have been treated successfully and have seen their debilitating conditions enter drug-free remission. Further study will be required as durability of remission is unclear at this time, but the current success of this treatment provides hope for those suffering from autoimmune diseases.
Sources:
'Gold rush' in cancer therapy for key type of bispecific antibody | STAT
What cancers can be treated with immune checkpoint inhibitors? | MD Anderson Cancer Center
Checkpoint inhibitor - Wikipedia
Lupus treatment breakthrough stems from cancer CAR-T therapy
October 2024 - Clinical Notes
By:
Karen Cunningham October, 30 2024
Clinical Notes – October 2024
The Race to Cure Alzheimer’s Disease
Alzheimer’s disease is a brain disorder that slowly destroys memory and thinking skills with eventual loss of ability to perform even simple tasks. It is believed to be caused by accumulation of amyloid and tau proteins in the brain that block communication between nerve cells. Scientists believe that a combination of genetic, environmental and lifestyle factors contribute to the cause. There are currently 6.7 million people over the age of 65 who are diagnosed with Alzheimer’s disease in the US and the incidence is expected to grow to 14 million by 2060. It is the fifth leading cause of death among Americans aged 65 and older. This disease disproportionately affects women and data has shown that Hispanic and African American populations have a higher probability of being diagnosed. The economic burden of caring for people with Alzheimer’s and other dementia was $345 Billion in 2023 and projected to be $1.5 to 1.6 Trillion by 2050.
Two new studies linked to Alzheimer’s have been released recently. The first study examined the use of semaglutide in patients with type 2 diabetes at initial diagnosis. The study included data from review of 116 million US patient electronic health records. Target trials were conducted on eligible patients with type 2 diabetes who had no prior Alzheimer’s diagnosis by comparing semaglutide with other anti-diabetic medications.
The results of this study demonstrated a 40% to 70% reduction in risk for first-time Alzheimer’s diagnosis group with use of semaglutide over 3 years when compared to other diabetes treatments such as insulin, metformin, SLCT2 inhibitors and other GLP-1 drugs.
The second study has uncovered a potential link between an infection caused by gut bacteria and the progression of Alzheimer’s disease. Research has discovered that Klebsiella pneumoniae; a common bacteria which often causes hospital-acquired infections can migrate from the gut into the bloodstream and eventually into the brain. This bacteria can cause inflammation in the brain tissue and impair cognitive functions resulting in symptoms commonly seen in Alzheimer’s patients. Hospitalizations and ICU stays, combined with antibiotic exposure may lead to further decline in microbiome diversity that increases the risk for older adults to develop not only digestive issues but also for extra-intestinal pathologies such as neurodegenerative disorders due to dysregulation of the gut-brain axis.
Research suggests that when antibiotics disrupt the gut, the result can lead to issues not just in the gut but also in the brain. The study using a preclinincal mouse model showed that antibiotic exposure depletes gut bacterial diversity and causes microbiome imbalance which in turn promotes proliferation of Klebsiella by creating a favorable environment. When this occurs, the Klebsiella bacteria can move from the gut into the bloodstream by passing through the gut lining and eventually reach the brain and triggering neuroinflammation and neurocognitive impairment.
The study is the first to show a direct correlation between Klebsiella infection and Alzheimer’s pathology, fueling the emerging field that investigates how infectious agents may trigger or aggravate Alzheimer’s disease. These findings support future research of how to treat harmful infectious agents in vulnerable populations such as the elderly or those recovering from sepsis.
The bottom line is that the human gut microbiome is a complex system developed in concert with numerous body functions to maintain balance and result in a healthy body that performs at maximal function. Through evolution, humans have significantly altered their diets with substitutions that include high amounts of sugar, chemicals and other compounds which have not only disrupted the natural balance of the gut causing endocrine diseases such as diabetes and other gastrointestinal issues but have now been found to impact development of neurodegenerative disease which is quite concerning.
Resources:
Ozempic linked to lower risk of Alzheimer’s diagnosis in new study
Researchers identify bacterial infection tied to Alzheimer's | MDLinx
July 2024 - Clinical Notes
By:
Karen Cunningham July, 19 2024
Clinical Notes – July 2024
Solution for Long COVID Continues to Elude NIH Researchers
The National Institutes of Health (NIH) launched a billion dollar research project in 2021 called RECOVER (Researching COVID to Enhance Recovery) with the goal of discovering what exactly is driving this complex disease process. Unfortunately, after three years of investigation and total funding of approximately $1.6 billion, the agency has only minimal data and many unanswered questions.
Long COVID or Post-COVID Conditions (PCC) is defined as an infection-associated chronic condition that can occur after SARS-CoV-2 infection and is present for at least three months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.
Based on ongoing research, some theories related to the cause have been proposed. One theory hypothesizes that after the immune system eliminates the coronavirus, some remnants survive in one or more organs and continue to elicit an immune response that may damage tissues resulting in chronic inflammation and subsequently long COVID symptoms. A second theory suggests that some viruses in the herpesvirus family such as the Epstein-Barr virus (that causes mononucleosis) from a prior infection may remain dormant but are reactivated after COVID infection. A third theory suggests that the immune system produces antibodies that target and attack a person’s own organs and tissues. The fourth theory suggests that symptoms of long COVID are due to damage to organs and tissues as a result of the initial immune response to SARS-CoV-2 infection.
Long COVID specialists and patients are frustrated with the lack of progress and critical of researchers because the current focus is on symptom management and is not addressing the cause on a molecular level. Another concern is the lack of clinical trials that assess potential pharmaceutical interventions. One physician that is participating in the RECOVER initiative commented that those critical of current research must be more realistic about how long it takes to thoroughly study a disease process which typically requires many years and billions of dollars to discover effective and safe treatments. Others argue that not enough is being done.
That is not good news for the 17 million Americans affected by long COVID and desperate to find a long term solution that will give them their life back. Those who have expressed criticism of how RECOVER is operating indicate that the researchers need to be more constructive and develop tools that result in positive changes to treatment. They feel that without change, the course of Long COVID cannot be altered since current symptom management has done little to affect the disease process.
Some steps for improvement have been suggested. First there must be better coordination among researchers. An advisory board inclusive of top US experts such as those physicians who have treated multiple patients can be important resources in investigation of this disease to discuss resource allocation as many of the researchers leading RECOVER are not experts in these types of conditions. The second recommendation is to shift focus from symptom management to extensive research of the biological mechanisms that are causing the long term consequences of the disease process to uncover treatments that will result in long term sustained remission of long COVID. The third recommendation is initiate more clinical trials and not continue to rely on observational studies that simply assess the progress of individuals following a specific treatment regimen. The alternative would be to study the multiple off-label drugs including antivirals, immunomodulators, antihistamines and anticoagulants which target the disease pathology but have yet to be investigated by the NIH. Only a few medications are being studied by the NIH, one being Paxlovid; an antiviral drug that failed to improve symptoms in its first trial to treat individuals with long COVID. The fourth recommendation is remove emphasis on soft therapies such as use of melatonin to counter sleep disturbance or exercise therapy that has been criticized by patients as being ineffective.
The financial impact of long COVID in the US is significant. In February of 2024, 6.8% of Americans aged 18 to 65 (over 17 million people) reported long COVID symptoms. Approximately 4 million of those people are unable to work. This represents 1.5% of the working age population. The economic impact of these lost wages is currently about $200 billion a year and is expected to rise. Factoring in the cost of medical care and lost quality of life, long COVID costs the US an additional $544 billion annually. This means that millions of Americans are dealing with frustrating and debilitating symptoms that make participation in day to day life more difficult.
It is imperative that long COVID research continues in earnest to address theoretical causes and initiate clinical trials to discover the best treatments as well as early preventative measures to end the suffering of so many people.
Sources:
How to Fix $1.6 Billion Long COVID Program: Experts Weigh In (medscape.com)
Long COVID (Post-COVID Conditions, PCC) > Fact Sheets > Yale Medicine
Clinical Overview of Long COVID | CDC
Long COVID: Another unexplained post-acute infectious syndrome? (harvard.edu)
April 2024 - Clinical Notes
By:
Karen Cunningham April, 16 2024
Clinical Notes – April 2024
Rate of Cancer Rising Among Younger People
Global statistics are confirming the trend of rising cancer diagnoses in people younger than age 50. Models based on global data have predicted that the number of early onset cancer cases will increase by approximately 30% between 2019 and 2030. Many oncologist are treating patients as young as teenagers for diseases that have typically affected people age 50 and older, yet past research could not explain why. New evidence has identified a significant factor in this trend; younger generations appear to be aging faster than their predecessors.
Research performed by a team of scientists at Washington University in St. Louis tracked data from 150,000 people between the ages of 37 and 54 using the U.K. Biobank which is a massive biomedical database. Nine blood-based biomarkers were used to calculate the individual biological age using the markers to determine the overall state of a person’s cells and tissues. Study results showed that people born after 1965 were more likely to have a biological age that outpaced their chronological age. Individuals identified with higher levels of accelerated aging had a 17% increase risk of developing any solid tumor cancer, with higher risk noted for lung, gastrointestinal and uterine cancers.
Another study from researchers at Brigham and Women’s Hospital in 2022 had revealed that the incidence of early onset cancers including breast, colon, esophagus, kidney, liver & pancreas has increased dramatically around the globe beginning around 1990. The data collected resulted in observation of what they called the birth cohort effect which showed each successive group of people born at later decades have a higher risk of developing cancer thought to be due to risk factors from exposure at a young age. What was alarming is that identified risk is increasing with each generation and predicted to continue to climb in successive generations. This team discovered that early life “exposome” which encompasses an individual’s diet, lifestyle, weight, environmental exposures and microbiome has changed substantially in the last several decades. They further hypothesize that factors such as the Western diet and lifestyle may be contributing to the rise in early onset cancer. Other potential risk factors related to early onset included alcohol consumption, sleep deprivation, smoking, obesity, type 2 diabetes, sedentary lifestyle and eating highly processed foods & sugary beverages all of which has significantly increased since the 1950’s. Researchers also found that adult sleep duration has not changed dramatically over several decades but children are getting much less sleep today than they were decades ago.
In the US, colorectal cancer which typically has affected men in their mid 60’s or older has become the leading cause of cancer death among men under 50 and ranks as the second leading cause of cancer death for young women.
In an effort to combat the alarming increase in rate of illness being found in younger people, the US Preventive Services Task Force recommended in 2021 that the time to begin colorectal screening should be changed to 45 years of age. The task force underwent an analysis of new peer-reviewed research that included investigation of the benefits and potential harms of screening. The evidence suggested that screening is both effective and saves lives. Previous guidelines for colorectal cancer screening that began in 1979 had recommended that people without risk factors for colorectal cancer begin the screening process at age 50 and continue about every ten years until age 75. This change was prompted by an increase in colorectal cancer diagnoses in younger people and of special concern was the increase in cases among Black Americans who are at higher risk of developing colorectal cancer early and dying from it. It has been noted that Black men and women are disproportionately affected both in terms of the development of colorectal cancer as well as lower survival rates.
Through early detection and standard treatment, such as colonoscopy and surgery, the 5 year survival rate of colorectal cancer increases up to 90%. Unfortunately, survival rate decreases sharply and economic burden increases once the disease has progressed into advanced stages due ongoing treatment with high cost specialty drugs often in combination regimens that do not lead to a cure.
Cancer prevention is the best opportunity to decrease deaths, yet communication from physicians and scientific researchers about the need for lifestyle and environmental changes has often fallen on deaf ears. The opportunity to make changes in lifestyle is a choice which can significantly impact both physical and mental health. The earlier that unhealthy changes are discontinued lessens the risk to develop serious diseases and chronic conditions that become more difficult and costly to manage without positive early interventions.
Now that accelerated aging has been recognized as a potential cause for early onset cancer and is predicted to continue on its upward trajectory, we can no longer ignore the risk factors that have been identified. To do so will negatively affect future generations and ultimately impact life expectancy around the globe.
References
Colorectal cancer screening should start earlier, at 45, panel says - STAT (statnews.com)
Colorectal cancer screening: 20 years of development and recent progress - PMC (nih.gov)
Cells of young are aging faster, study finds, in possible cancer link (statnews.com)
Why are so many young people getting cancer? What the data say (nature.com)
Researchers report dramatic rise in cancer in people under 50 — Harvard Gazette
January 2024 - Clinical Notes
By:
Karen Cunningham January, 22 2024
Clinical Notes – January 2024
Telehealth for Big Pharma?
Healthcare delivery has seen some significant changes that occurred more quickly than in the past as a result of the impact of the COVID 19 pandemic. Access to reliable and affordable treatment has been and continues to be a problem in the USA but never more apparent and in the public eye than during the pandemic.
One positive change was the addition of telehealth visits. This underutilized method of patient care would allow people who were limited by lack of available providers in their geographic area or other access barriers such as transportation to participate in online physician visits. Telehealth allowed physicians to address health concerns of many people without emergency department visits at a time when hospitals were overflowing with people diagnosed with COVID 19. These visits also improved access for those with mental health conditions having difficulty finding a provider who would accept new patients in their area.
Now, drug manufacturer Eli Lilly has announced a new platform called LillyDirect which allows patients direct access to physicians using telehealth to obtain and fill prescriptions for the drugs they manufacture. The platform soft launched in March 2023 and is reported to be the most robust digital pharmacy solution currently available. At this time, their platform contains three conditions; obesity, diabetes or migraine headaches. Patients simply need to click on the condition pertinent to them and the system will route them to telehealth sites that are able to prescribe one of Lilly’s drugs to them if they are eligible. The timing of their announcement could not be better for the drug manufacturer who just launched the new GLP-1 obesity drug Zepbound in December 2023.
GLP-1 drugs rapidly gained popularity primarily due to successful weight loss noted in clinical trials as well as frequent advertisement in mass media. This led to high demand for these drugs resulting in shortages despite poor insurance coverage and in some cases no coverage at all.
Lilly’s program can direct patients without a prescription to telehealth provider 9amHealth while those who already possess a prescription can transfer that script to online pharmacy Truepill. Included in the transaction is the automatic application of manufacturer coupons for this costly drug so that patients with insurance coverage of Zepbound may see monthly cost of $25.00 and those without insurance about $550.00 (approximately half the list price.) LillyDirect also provides support in developing prior authorizations to gain insurance coverage approval which is often an obstacle for those seeking treatment with these drugs.
An added bonus for the drug companies is that they will gain valuable patient health data that has not been accessible to them in the past which can influence their research and development as well as marketing capabilities.
Other drug companies offer similar programs. Pfizer launched a program to enhance access to Paxlovid last year that directs patients to telehealth provider SteadyMD. AbbVie has a program for dry eye and irritable bowel syndrome treatments.
Drug companies are promoting these online programs as a mechanism to assist patients by allowing easy access to care but should we be concerned about patients dealing with drug manufacturers directly? The drug manufacturers indicate they have drawn a clear line between their companies and the telehealth providers who prescribe their drugs and further state they are not involved with treatment or prescription decisions. They go on to emphasize that telehealth providers are independent and use their clinical judgement to determine if a drug is appropriate for each patient.
Critics are concerned that these type of platforms may place profits ahead of comprehensive care by overlooking the potential use of non-pharmaceutical treatment options. Some physicians are concerned that providers devoted to a drug company and their products would not act in the best interest of the patient whereby the best drug for that patient may be a drug from another manufacturer so would the provider actually prescribe the best drug or the one made by the company they represent?
If these programs provide drugs at a lower cost due to direct rebates, assist patients in obtaining the drugs they need and are easy to use, it is likely that they will be readily adopted by consumers.
Prior Authorization Requests
A new rule applicable to health insurance companies that offer Medicare, Medicaid, Children’s Health Insurance Program & Obamacare plans regarding specific reasons for denying coverage and designed to shorten the preauthorization process is to become effective in 2027. Insurers will be required to return urgent requests within 72 hours and non-urgent requests within 7 days.
Physicians view prior authorization as a hindrance to patients receiving care in a timely manner. Insurers state that prior authorization is crucial to assuring that patients receive appropriate care, avoid unnecessary treatment and be cost effective. In addition, insurers view this process as a mechanism for fraud prevention.
Included in the new rule are tech requirements that would improve the flow of information between health systems’ records and insurers’ authorization systems. This should result in less time spent entering patient data that one party has but the other does not as well as better decision making due to insurers having access to all pertinent patient data such as prior treatments that were ineffective leading to recommendation for the current treatment plan.
References:
Eli Lilly, Pfizer, and others want in on the online prescription market (statnews.com)
Online Pharmacy Services Option for Lilly Medicines | LillyDirect™
Prior authorization will have to move faster under new Biden rule (statnews.com)
October 2023 - Clinical Notes
By:
Karen Cunningham | October, 31 2023
Clinical Notes – October 2023
Factor XI Inhibitors Used as Anticoagulants
For over seventy years, prophylactic administration of anticoagulants for people diagnosed with atrial fibrillation, venous thrombosis and pulmonary embolism has been prescribed to prevent thromboembolic disorders. Anticoagulation continues to be the standard treatment today and can be utilized alone or in combination with thrombolytic agents such as urokinase, streptokinase or tissue plasminogen. (Thrombolytic agents are typically indicated for treatment of acute heart attack, pulmonary embolism or stroke.)
One of the main problems associated with anticoagulation relates to the numerous clotting factors that affect two different aspects of blood clotting regulation. One aspect is the anticoagulant system which consists of four enzyme pathways that reduce or limit thrombin production and activity, preventing excessive clot formation. The other aspect is the clinical pathway which is a suggested course of action for atrial fibrillation, coronary artery disease or venous thromboembolism. Anticoagulants block one of these factors to prevent clotting but also can cause bleeding.
Clinical research revealed that factor XI has a unique mechanism in the clot formation process in that it is important to clot formation but does not seem to have a major role in the ability to heal and repair blood vessels. In other words, factor XI may prevent the formation of thrombosis while allowing formation of thrombin for natural hemostasis to prevent bleeding. This theory correlates with epidemiologic data suggesting that patients with genetic factor XI deficiency have low rates of stroke and myocardial infarction but don’t appear to bleed spontaneously.
Several factor XI inhibitors are now in clinical development. Three drugs that showed the most promise for this indication are abelacimab; a monoclonal antibody administered by subcutaneous injection on a monthly basis being developed by Athos Therapeutics and two small molecules (drugs with low molecular weight organic compound) that can be administered orally; milvexian being developed by Bristol Myers Squibb in collaboration with Janssen and asundexian being developed by Bayer.
The Azalea-TIMI 71 trial was designed as a phase 2b, multicenter, randomized, active-controlled study to evaluate the safety and tolerability of two blinded doses of abelacimab compared with open-label rivaroxaban (Xarelto) in patients with atrial fibrillation at moderate to high risk for stroke. This trial was stopped early due to an unprecedented bleeding benefit for adults with atrial fibrillation when abelacimab showed reduction in major bleeding vs a direct oral anticoagulant. The Azalea trial is noted to be the largest and longest head to head study of the ability of a factor XI inhibitor to provide significant reduction in bleeding as compared to standard anticoagulation treatment protocols. The full results of Azalea-TIMI 71 will be presented at an upcoming scientific conference according to the release by Athos on September 18,2023.
If the FDA approves abelacimab as a safe and effective prophylactic measure to prevent thromboembolic events, its use should also result in a significant decrease in bleeding episodes that can lead to other serious conditions for people who require this treatment.
Resources:
Factor XI Inhibitors: Promise of a Safe Anticoagulant? (medscape.com)
2023-09-18 Anthos Press Release final (anthostherapeutics.com)
Abelacimab for Prevention of Venous Thromboembolism | NEJM
The evolution of anticoagulant therapy - PMC (nih.gov)
Abelacimab trial for AF stopped early due to ‘overwhelming’ reduction in bleeding (healio.com)
July 2023 - Clinical Notes
By:
Karen Cunningham | July, 31 2023
Clinical Notes – July 2023
Cancer Drug Shortages
Roughly 2M Americans are expected to receive a cancer diagnosis in 2023.
Oncologists are being forced to prescribe less than ideal regimens instead of standard treatment regimens known to be effective due to current shortages of Methotrexate; used to treat breast and soft tissue cancers, Cisplatin; used to treat testicular, ovarian, bladder, head/neck, lung and cervical cancers, Fluorouracil used to treat skin cancer, breast cancer, gastric cancer, pancreatic cancer and often the first line treatment for colon/rectal cancer and Carboplatin; used to treat ovarian cancer and in low supply due to lack of Cisplatin which resulted in increased use for breast cancer. These alternate regimens are typically not as effective and often have more severe side effects than the older drugs.
These drug shortages present an ethical and moral dilemma for oncologists who must decide which patients will be treated with a standard regimen for their disease and which will have to settle for a less than optimal regimen or wait until the drug becomes available. It has become of particular concern when treating children.
In addition, changes in treatment regimens impact patients who have had success with their initial treatment only to be advised that they cannot complete the planned regimen due to a drug shortage. These patients must opt for either an alternative drug that may be less effective or result in severe side effects and toxicity or forego treatment and hope that the next scans do not show any cancer growth, all while dealing with their cancer diagnosis and associated fears that remission will not be achieved and they will die.
The underlying cause of the shortage is related to the economics of the generic drug market whereby hospitals and producers emphasize the need for low costs to improve profits without consideration of a reliable drug supply. Simply put, hospitals are not willing to pay enough to have a resilient supply chain. This led to less interest for drug manufacturers to continue to produce these drugs when profitability is so low and to focus on new blockbuster drugs that are highly profitable. But what about the moral responsibility of US healthcare systems and the pharmaceutical manufacturers have to patients fighting a life threatening disease?
The current shortage of oncology drugs is attributed to the shutdown of Intas Pharmaceuticals in India. According to reports, FDA inspectors in November of 2022 found a garbage truck filled with shredded documents as the drug supplier was attempting to delete evidence of quality control issues. Intas had been supplying about one half of the US Cisplatin supply so the flow of key drugs was slowed. Hospitals fearful of the inability to obtain these drugs began to stockpile them which exacerbated the problem further.
There are some solutions to drug shortages such as a cooperative effort between hospitals and the federal government to develop a reserve inventory of essential medicines that hospitals can join to have access to necessary drugs. Another option could be redirection of the relationship with their general purchasing organization or GPO currently used to negotiate drug prices. Instead of focusing on the lowest possible cost, they could use their buying power to leverage implementation of transparency, reliable supplies and assure quality assurance monitoring (concerns important to hospitals,) knowing that negotiated costs would be higher to support these services yet the benefit would be no drug shortages. Reasonable increases in allowed costs for drugs may also entice manufacturers to invest in increased production of essential drugs and possibly more plants in the US which would be a boost to the economy as well.
Economists have suggested that many manufacturing breakdowns occur due to lack of soft systems and skills to run an operation smoothly and not because of equipment failure. Rating quality metrics is the first part of the solution to develop quality management maturity. Next is to begin rating hospitals on proactive actions they take when there is no shortage such as purchasing drugs from manufacturers that have high quality metrics and participation in supply chain resilience programs both of which would result in a higher rating for the individual hospital. Higher ratings would then transform into a cash reward at the end of each year for the hospitals adopting this type of program.
Drug cost and availability have been a problem for many years and will continue unless some new measures are implemented that provide necessary drugs at a reasonable cost to all Americans. Curing disease and promoting the health of all humanity should be the primary reason to develop and distribute life-saving drugs not profitability.
Misdiagnosis Causes 800K Deaths and Serious Disabilities Annually in US
Current estimates indicate that about 371,000 people die annually and about 424,000 people suffer a permanent disability or serious harm after being misdiagnosed. Diagnostic errors are caused by overlooking a disease, concluding that the symptoms and current condition of a patient are due to another diagnosis or providing a late diagnosis that impacts the care to treat the actual condition in a timely manner.
According to a 2015 report by the National Academy of Medicine, there have been few attempts to quantify misdiagnoses as related to death and permanent disability. It also notes that the full impact of these qualifiers is underestimated by the medical community. The study further states that fifteen diseases account for half of misdiagnoses and five of these diseases; stroke, sepsis, pneumonia, venous thromboembolism and lung cancer caused 300,000 cases of serious harm or about 40% of total misdiagnosis.
The main reason for misdiagnosis is cognitive error by the physician. This can be due to lack of typical signs or symptoms associated with a disease or common symptoms not usually associated with severe disease but are precursors to a more serious condition that is developing before full blown symptoms are evident. An example given was a patient presenting with dizziness which is a symptom that occurs in the majority of cases of stroke, but only very few cases of dizziness result in a stroke. Another reason can be physician bias such as dismissing a diagnosis of stroke in a young patient simply because it is exceedingly rare.
The most frequently misdiagnosed condition is stroke which prompted testing of an AI (artificial intelligence) solution to improve stroke diagnosis. Many patients evaluated for headache and dizziness in the ED are discharged and advised the symptoms will resolve by the time they get home. Unfortunately in some cases, the evolving stroke that could have been managed in the ED earlier resulting in cost of about $10k now must be managed with acute care admission that can result in claims in the $100k range. In addition to higher claim costs, the stroke diagnosis also presents with other concerns such as societal cost due to lost productivity because of death or disability.
Federal research funding to improve diagnostic capability is very limited. Proponents of developing the ability to diagnose the correct disease are certain that improvement is achievable as are significant savings, but also caution that increases in second opinions, extra testing and additional care provided to patients will generate some cost that offsets the savings. However, the prospect of saving lives and preventing serious long term disabilities is good reason for pursing diagnostic excellence.
Resources
Cancer drug shortages worry patients, doctors over survival odds (statnews.com)
The cancer drug shortage isn’t new — and neither are the solutions (statnews.com)
Can U.S. cancer drug shortages be fixed? (statnews.com)
In a bid to overhaul pharma supply chain, Civica Rx starts selling first generic drug (statnews.com)
Study: Misdiagnosis causes 800,000 deaths, serious disabilities a year in U.S. (statnews.com)
April 2023 - Clinical Notes
By:
Karen Cunningham | April, 17 2023
Clinical Notes – April 2023
Shortage of Cancer Drugs Continues to Disrupt Care
1 in 2 women and 1 in 3 men in the US will develop cancer in their lifetime. In 2021 there were approximately 1.9 million new cases of cancer diagnosed and 608,570 cancer deaths in the US. The battle against cancer has been waged for decades with history of chemotherapy in the early 20th century.
The era of cancer chemotherapy began in the 1940s. During World War I & II, soldiers exposed to mustard gas demonstrated decreased levels of leukocytes or white blood cells. This led to the use of nitrogen mustard as the first chemotherapy to treat lymphomas in 1943. In the years that followed, new drugs were developed some synthetically and some from plant sources.
The drug shortages according to FDA analysis presented to congress in June 2018 identified three root causes for drug shortages:
· Lack of incentives for manufacturers to produce less profitable drugs
· The market does not recognize and reward manufacturers for mature quality systems that focus on continuous improvement and early detection of supply chain issues; and
· Logistical and regulatory challenges make it difficult for the market to recover from a disruption
The persistency of drug shortages whether cancer drugs or other medicines is in part due to the globalized pharmaceutical supply chain. The most significant shortage in the US is of active pharmaceutical ingredients or API which form the base of drugs that have added ingredients to manufacture the final product. These base ingredients are primarily manufactured in China and India.
The COVID 19 pandemic has also impacted drug production with the addition of supply chain issues which has further delayed the manufacturing process since 2020.
Oncology drugs currently in short supply include:
· Methotrexate used to treat breast and soft tissue cancers
· Cisplatin used to treat ovarian, testicular, bladder, head and neck, lung and cervical cancers
· Pluvicto used to treat PSMA; positive metastatic castration resistant prostate cancer
· Bacillus Calmette-Guerin or BCG used to treat bladder cancer
· Fluorouracil used to treat breast cancer, colon/rectal cancer, gastric cancer & pancreatic cancer
The shortages have resulted in treatment delays, reduced doses or alternative regimens that are often higher cost drugs. It also forces many oncologists to make ethical treatment decisions based on availability as to whether the supply they have is given to someone newly diagnosed or someone favorably responding to the drug but not near completion of a standard regimen.
Once again patients are forced to endure treatment delays that may result in disease progression or higher treatment costs due to the lack of known drug regimens that may be older treatments, but are still very effective for certain types of cancer. Perhaps the pharmaceutical industry can be persuaded to focus on manufacturing these known lifesaving drugs by discovering how to improve the supply chain and access to API so patients may once again count on the availability of a critical weapon in the battle against Cancer.
FDA Approved Status Change of Naloxone Nasal Spray
Naloxone (Narcan) was originally developed as an injectable opioid antagonist to reverse drug overdose due to opioids only and was made available in 1971. This drug was used mostly by EMTs and in clinical settings but in October 2010, the Quincy Police Department in Massachusetts began distribution to officers who often were the first responders to an emergency call related to drug overdose. In 2013, the Deputy Director of the US National Drug Control Policy advocated that all law enforcement agencies carry Naloxone and subsequently many agencies began to distribute Naloxone to their officers as well.
The first opioid epidemic in the US occurred during the Civil War when wounded soldiers were treated with opium gum, laudanum or morphine for pain from gunshot wounds or other injuries but also for cough, diarrhea, PTSD and depression indicative of misapplication of these drugs resulting in subsequent addiction.
Our current opioid crisis began in the 1990s attributed primarily to the overuse of OxyContin coupled with false advertising from Purdue Pharma indicating that OxyContin was less addictive than other immediate release pain medications. Purdue Pharma even paid some physicians to provide educational discussions with other healthcare providers but it is suggested that the reality of these payment was to encourage physicians to prescribe OxyContin more frequently. Purdue settled with the US government on March 3, 2022 for up to $6B.
Purdue was also found to have paid kickbacks to Practice Fusion; a web based electronic health record company that admitted to solicitation of a major opioid company to utilize software developed by Practice Fusion that was designed to influence prescription of opioid pain medications in physician practices. Practice Fusion settled their case with the Department of Justice on January 27, 2020 for $145M to pay for resolution of criminal and civil investigations.
Naloxone became available as a nasal spray after achieving approval from the FDA in 2015 as a prescription drug. It was then recognized by the FDA in November of 2022 as a safe and effective over the counter drug prompting recent approval for use without a prescription in February 2023. This approval will allow anyone to legally purchase Naloxone to prevent opiate overdose. Increased access to Narcan can be a life saving measure for those still battling opioid addiction and for accidental overdoses.
Sources:
Can U.S. cancer drug shortages be fixed? (statnews.com)
History of Cancer Treatments: Chemotherapy
Shortage on 4 cancer drugs creates dire scenarios for patients (nbcnews.com)
Assessment of the Evolution of Cancer Treatment Therapies - PMC (nih.gov)
FDA Approves First Over-the-Counter Naloxone Nasal Spray | FDA
Doctoral candidate explores the nation’s first opioid epidemic | Binghamton News
The History of Opioid Addiction - The Long Opioid Drug Crisis (whisperingoakslodge.com)
What led to the opioid crisis—and how to fix it | News | Harvard T.H. Chan School of Public Health
National Settlement with Purdue Pharma and Sacklers | News | NH Department of Justice
January 2023 - Clinical Notes
By:
Karen Cunningham | January, 13 2023
Clinical Notes – January 2023
FDA Approves Alzheimer’s Drug Leqembi
Alzheimer’s disease is a progressive type of dementia that affects memory, thinking and behavior in approximately 6.5 million people in the USA. Brain cell connections as well as the brain cells themselves degenerate and die resulting in symptoms of dementia. Scientific research has determined the cause of this debilitating condition to be the result of abnormal accumulation of amyloid and tau proteins. Amyloid develops into plaques around the brain and tau deposits form tangles within the brain resulting in symptomology. Current drug therapy works to restore the balance of neurotransmitters in the brain but cannot cure the disease although use of these drugs have shown improvement in memory, awareness and function.
Leqembi (Lecanemab) developed by Japanese pharmaceutical company Eisai has received accelerated approval for the treatment of Alzheimer’s disease on January 6, 2023. A large clinical trial (Clarity-AD phase 3) published in November 2022 showed that Leqembi moderately slowed cognitive and functional decline in people with early stage disease by 27%. The 18-month study of 1,800 participants also demonstrated reduced levels of beta-amyloid which is a toxic protein in the brain believed to cause progression of Alzheimer’s and noted to be the secondary goal of the trial that showed reduction of toxic plaques in the brain resulted in slowing patients’ decline on three measures of memory & function.
The Clarity AD trial was the largest study conducted to date that tests the long debated theory that clearing toxic amyloid brain plaques might delay the progression of Alzheimer’s by slowing the pace of memory loss thereby delaying the onset of dementia.
The news that an experimental drug for Alzheimer’s treatment has demonstrated better preliminary clinical results in the Clarity AD trial has long been awaited by the millions of people currently suffering with this debilitating disease and has created hope for these individuals and their caregivers. Input from patients and families affected by the disease indicate they feel that any treatment which will delay further cognitive decline even for a short period of time will provide benefits to the individual patient. However, some physicians remain skeptical as they feel the small gains noted in the study will not be clearly appreciable in many patients. This skepticism may result in reluctance to prescribe Leqembi.
In addition, treatment with Leqembi does not come without risks. Approximately 21% of patients treated with this drug experienced brain swelling or brain bleeding that was visible on PET scans; a noted side effect with this type of drug, but only 3% of those patients were symptomatic. Also notable is that 10% of people carry two copies of the APOE4 gene which has the ability to decrease risk for Alzheimer’s disease so they would not benefit from this drug therapy plus it has the potential to harm these patients. Unfortunately, one copy of APOE4 will increase risk for Alzheimer’s.
Another study called The Ahead Trial is testing Leqembi in people who are not experiencing any signs of Alzheimer’s disease yet have plaques of amyloid protein buildup in their brains. If trial results are successful, experts believe treatment will provide the biggest benefit when initiated as early as possible for these individuals. There is no evidence that it will help people with moderate or late stage Alzheimer’s and unclear how long any benefit will last.
Eisai will co-market Leqembi with Biogen under a long standing partnership. For Biogen, this is seen as an opportunity to repair their reputation after the debacle that ensued when Biogen’s Aduhelm was approved in 2021 and resulted in backlash due to cost ($56K annually) for the drug & lack of demonstrable improvement in cognition of study participants. Eisai has set the price of Leqembi at $26,500 annually for an average weight person. Leqembi could become a potential blockbuster for both Eisai & Biogen if Medicare agrees to pay for this drug since the majority of people with Alzheimer’s disease are Medicare participants. It will become available to physicians starting 1/16/2023. The decision for Medicare reimbursement is slated for later this year leading to slow roll out expectations. ICER (Institute for Clinical and Economic Review) has evaluated Leqembi & determined that the drug would only be cost-effective if priced between $8,500 to $20,600 per year.
Alzheimer’s disease was first discovered in 1906 and although it has been studied for many years, no significant treatment has yet to be identified. What we do know is that it quickly robs individuals of their very essence which impacts both the patient and their families as they struggle with providing constant supervision and detailed hands on care to a person who doesn’t even recognize themselves or their loved ones. It makes it easy to understand why treatment that provides even incremental positive changes in cognition would be a welcome prospect.
UK Plan for Viral Sequencing of Common Seasonal Respiratory Viruses
The Respiratory Virus & Microbiome Initiative launched recently in the United Kingdom to begin viral sequencing in an effort to identify the evolution of SARS-CoV-2, other coronaviruses, flu families, RSV and other common pathogens that typically cause minor symptoms but are responsible for leading to high volume of illness annually. The goal of researchers is to enable better monitoring of viruses in the UK for evidence of mutations, the emergence of new viruses and to generate high volumes of data for research that will hopefully lead to development of vaccines and therapeutics. It will allow scientists to gain a better understanding of these viruses such as rhinovirus or adenovirus which historically have not been monitored as closely as other viruses but could be a key to successful treatment.
Viral sequencing can be performed using genomic sequencing to decode the genetic material found in an organism or virus. These sequences are compared to assist with tracking of viral transmission whether from country to country or in a hospital, assist in determination of whether mutations are noted and determine how these changes might affect public health.
It is important to note that all viruses mutate as they replicate and spread across a population. Viruses with RNA as genetic material such SARS-CoV-2 and those causing influenza have the ability to mutate considerably faster than viruses with DNA. Each time SARS-CoV-2 replicates there is an opportunity for changes to occur. However, many times these changes do not have affect upon the virus’s ability to spread or cause disease because there is no alteration in the major proteins involved.
The plan design is intended to build an infrastructure to enable routine viral surveillance that can also be deployed in another epidemic or pandemic. The program should be workable at a low cost and with the intention of inspiring other research teams worldwide to adopt similar protocols as well as encourage sharing of all methods and computational software.
A cure for the common cold has long eluded science and medicine. Since most symptoms experienced while ill with a cold are uncomfortable and annoying but not usually lethal, there is less interest in pursuing research particularly since treatment through symptom management is available at a relatively low cost. However, it is possible that new data and theories could be developed to manage all types of viral infections and eventually provide a cure that would improve many lives.
Sources:
FDA approves new Alzheimer's drug Leqembi (statnews.com)
New case study details death in closely watched Alzhiemer's trial (statnews.com)
For Alzheimer’s patients in successful trial, a feeling of gratitude (statnews.com)
Alzheimer’s treatment slowed cognitive decline in closely watched trial (statnews.com)
The FDA Approved The New Anti-Alzheimer’s Drug Leqembi. What You Need To Know (forbes.com)
Covid showed the power of viral sequencing. The U.K. plans more. (statnews.com)
November 2022 - Clinical Notes
By:
Karen Cunningham | November, 22 2022
Clinical Notes – November 2022
Growing Need for New Antibiotics
Antibiotic-resistant infections already kill greater than 48,000 Americans and sicken 2.8 B people per year according to the Centers for Disease Control (CDC.) The annual global death toll is 1.7 M and antibiotic resistance worsened during the pandemic across the US and not just with individual outbreaks. The World Health Organization (WHO) analyzes the current antibiotic pipeline and had concluded in 2021 that minimal progress has been made in development of new antibiotics necessary to treat drug resistant infections. The growing number of catastrophic claims attributed to sepsis is indicative of this trend.
Large pharmaceutical companies that formerly led the manufacture of antibiotics have shown diminished interest in antibiotic development and production primarily due to significantly lower income achieved when compared with new cardiovascular or diabetes drugs and the huge income potential of new cancer drugs. In part, the lower income is due to fewer people requiring antibiotics compared to other drugs taken on a daily basis for long term duration.
An economic study completed in 2016 revealed that the costs to bring a new drug to market including a new antibiotic is $1.4 B which means that a new antibiotic would have to earn $300 M per year to break even. However, data has shown that few antibiotics generate sales of $100 M annually.
Since the exit of the large pharmaceutical firms, development and manufacturing of new antibiotics had drawn the attention of small biotech companies. In 2010, five of every fifteen of these biotech firms that developed new antibiotics approved by the FDA have folded or sold themselves at auction because they did not have the income to maintain solvency during the lag period between approval and earnings.
New legislation to address the multiple concerns of antibiotic resistance has been submitted to Congress for review. The Pasteur Act (Pioneering Antimicrobial Subscriptions to End Upsurging Resistance) if approved could provide financial assistance through government funding to develop and manufacture some new antibiotics. The proposal has received bipartisan support in both the House and Senate and is backed by the Department of Health & Human Services (HHS) as well as being endorsed in the last White House budget.
The Pasteur Act commits to funding $6 B over several years for a program to create a plan for antibiotic development that will be overseen by a panel of experts within HHS. Current low level funding means that only a few new antibiotics may be developed initially but if the program is successful, it could be reauthorized with a higher budget which would impact development of more drugs. According to the CDC, the US presently spends $4.6 B every year to respond to antibiotic resistant infections.
There is opposition to the Pasteur Act and comments have been made calling it a “blank check to pharmaceutical manufacturers” but it is important to remember that the small biotech firms willing to provide new antibiotics crucial to the battle against drug resistant infections are not part of Big Pharma; a group under considerable scrutiny in recent years due to exorbitant drug pricing.
Nevertheless, if/when a new superbug is discovered and there are no drugs to manage the infection, humanity may pay the ultimate price.
New Brain Implants Designed for Communication
Results from two new studies show that scientists have created a process where new brain implants can read words directly from the brain and translate this internal speech into external signals, thereby allowing communication for people with diseases that blocked their ability to talk or type.
Currently some people with the inability to speak due to brain injury or disease can use devices that are operated by small movements such as eye gaze but not all people have this ability. New studies that focused on internal speech and only require the person to think were pursued.
Neuroscientists at Caltech developed a device that predicts internal speech directly and allows the person to just concentrate on saying a word inside their mind which is transformed into text. Neural signals associated with words are detected by electrodes implanted in the brain and allow translation into text that is made audible by computer programs designed to generate speech.
While this technology is in early stages of development, the goal to restore communication and mobility would certainly improve the lives of many individuals living with the inability to speak.
Sources:
The $6 Billion Shot at Making New Antibiotics | WIRED
WHO report highlights shortage of new antibiotics | CIDRAP (umn.edu)
New brain implants ‘read’ words directly from people’s thoughts (sciencenews.org)
August 2022 - Clinical Notes
By:
Karen Cunningham | August, 15 2022
Clinical Notes – August 2022
Two Children Die After Treatment with Zolgensma
Novartis Pharmaceuticals recently reported that two children developed acute liver failure and have died after receiving Zolgensma gene therapy. The children from Russia and Kazakhstan perished five to six weeks after receiving the gene therapy via a one-time infusion. Also notable is that tapering of corticosteroid therapy had occurred between one and ten days prior to their deaths. Tapering of corticosteroids is part of the regimen to promote proper liver function.
Zolgensma product labeling includes a warning of serious acute liver injury and acute liver failure with elevated aminotransferases (liver enzymes) and warns that patients with pre-existing liver impairment may be at higher risk. It further states that systemic corticosteroids must be administered to all patients before and after infusion of Zolgensma and that liver function must be monitored for at least three months after infusion.
These are the first fatalities associated with liver failure as there were no liver related deaths reported during clinical trials. There was one death reported due to respiratory failure six months after receiving Zolgensma in the STR1VE-US Trial but was found to be due to underlying spinal muscular atrophy (SMA) and unrelated to treatment per the investigator. Two other children died after receiving Zolgensma; one participated in the STR1VE-US Trial & one participated in the STR1VE-EU Trial. Both deaths were deemed unrelated to the treatment based on autopsy findings.
Novartis has contacted regulators in the US and other countries and plans to update labeling to specify that acute liver failure has been reported. The impact and cause of these deaths may influence physicians and payers to become more cautious about using Zolgensma, particularly when another alternative; Spinraza is available albeit not a cure for SMA.
Zolgensma has been administered to more than 2,300 patients worldwide and generated income of $469M in the US and $1.35B globally.
FDA Approved Rethymic for Treatment of Pediatric Congenital Athymia
Congenital athymia is an ultra-rare immune disorder caused by a child being born without a thymus. The thymus is an organ located at the top of the heart and produces T-cells or specialized white blood cells that fight infection; particularly viral infections. These children have severe immunodeficiency and immune dysregulation. Incidence is estimated to be about 17-24 live births per year in the US.
Rethymic is categorized as an immunostimulating agent and is engineered from human thymus tissue collected from a donor. This tissue is collected as individual slices and dosage is based upon body surface area of the patient. It is delivered in a single surgical procedure by implantation into the quadriceps muscle with maximum dose of 42 slices. It is designed to regenerate the thymic function in children with congenital athymia and does not require donor-recipient matching.
Rethymic has been studied across 10 clinical trials for more than 25 years. Prior to development of Rethymic only supportive care was available resulting in death by age two or three. Cost of this one-time treatment Rethymic ranges from $2.9M - $6M.
Sources for Clinical Notes August 2022
Package Insert - ZOLGENSMA (fda.gov)
April 2022 - Clinical Notes
By:
Karen Cunningham | April, 25 2022
Clinical Notes – April 2022
Artificial Intelligence in Healthcare
The origin of modern artificial intelligence (AI) has been found in attempts by classical philosophers to describe human thinking as a symbolic system. The first AI program called the Logic Theorist was developed in 1956 at a conference at Dartmouth College by Alfred Newell, J.C. Shaw and Herbert Simon to find basic equations of logic as defined in Principia Mathematica by Bertrand Russell and Alfred North Whitehead.
Applications for AI have been proposed and studied for years to provide a positive impact to many industries. The cornerstone of AI is to build intelligence into machines that allow the machine to comprehend, sense, learn and act like humans, to the extent that they can perform human tasks with precision.
The healthcare arena is an environment that has a multitude of collected health data that can be used to develop AI platforms which will enable machines to perform a number of clinical and administrative healthcare functions for specific treatment related purposes. AI as an industry in healthcare is expected to grow in size and income from $4.9B in 2020 to $45.2B by 2026.
AI-assisted robotic surgery began in 1985 and has helped improve surgical performance that leads to shorter hospital stays, reduced pain and discomfort, faster recovery time and return to normal daily activities, smaller incisions, reduced blood loss and minimal scarring.
Throughout 2022, hospitals will be evaluating the effectiveness of infection prevention and control programs particularly in light of the COVID pandemic. AI is expected to help monitor patients in real time to provide quicker infection risk identification resulting in initiation of the correct treatment faster than the current process.
Other applications include machines that can detect disease and identify cancer cells, help analyze chronic conditions with lab and other medical data to ensure early diagnosis and AI is utilized for new drug discoveries by using a combination of historical data and medical intelligence.
There are many vendors currently building programs to utilize the power of AI to project future claim costs. Medical Risk Managers is participating in pilots with some of these vendors hoping to partner with a chosen vendor in 2023 to expand our robust underwriting capabilities. Like many industries, we understand that AI will be part of our future. We feel the key is to integrate with current technologies in the most efficient and effective manner.
Comprehensive analysis of healthcare data will allow decision makers to use the conclusions from AI analysis to make improvements in patient outcomes, reduce cost and boost staff job satisfaction. All welcome changes in an industry that has been weathering the complexities and hardships of a pandemic environment.
Gene Therapy Approvals on the Horizon for 2022
Roctavian – treatment of hemophilia A; BioMarin completed required phase 3 clinical trial and expects to submit a BLA in Q2 of 2022 which means there is potential for FDA approval in 2022 but more likely to occur in early 2023. Expected cost is $3M-$5M.
Etranacogene dexaparvovec – treatment of hemophilia B has review for approval possibly 10/1/2022 but more likely in 12/2022. Expected cost is $3M-$5M
LentiGlobin – treatment of sickle cell disease has review for approval in Q1 2023. Expected cost is $1M.
Beti-cel – treatment of beta thalassemia anemia with revised review date of 8/19/2022. Expected cost is $2M
Eli-cel – treatment of cerebral adrenoleukodystrophy (CALD) with revised review date of 9/16/2022. Expected cost is $2M
References:
https://appinventiv.com/blog/healthcare-app-trend
The Ten Hottest Medical Technologies - What to Know (medicaltechnologyschools.com)
Seven predictions for healthcare technology trends in 2022 | Wolters Kluwer
Artificial Intelligence Applications | Most adopted AI Technologies (educba.com)
A Brief History of Artificial Intelligence | Live Science
Seven predictions for healthcare technology trends in 2022 | Wolters Kluwer
Healthcare trends that will reshape the industry in 2022 (appinventiv.com)
5 FDA decisions to watch in the second quarter | BioPharma Dive
Pharmacy Focus: Pipeline Therapies to Watch through 2022 (hmig.com)
bluebird Provides Update on FDA Review Timelines for Betibeglogene Autotemcel (beti-cel) for Beta-Thalassemia and Elivaldogene Autotemcel (eli-cel) for Cerebral Adrenoleukodystrophy (CALD) (yahoo.com)JPM 2022: Bluebird bio hopes for clear skies ahead as it gears up for trio of gene therapy launches | Fierce Pharma
January 2022 - Clinical Notes
By:
Karen Cunningham | January, 31 2022
Clinical Notes – January 2022
Mark Cuban CostPlus Drug Company Launches Online Pharmacy
Well known entrepreneur and investor Mark Cuban has announced the launch of his new company on January 19, 2022 that may become the tipping point for drastic changes to generic pharmaceutical pricing. Mr. Cuban’s comments about generic drug cost pricing being ridiculous and lacking transparency to consumers have appeared in the media. The mission of his new company is to provide access to safe and affordable medications to all Americans regardless of whether they have insurance coverage or not.
A Gallup poll released in September 2021 showed that 18 million Americans are unable to afford at least one physician prescribed medication in the previous three months. Studies also found there are many conditions for which people from disadvantaged populations are suffering that can be successfully treated with current drug therapy, however pricing per course of treatment prohibited these people from seeking treatment.
A pharmacy benefit manager operation or PBM is being established in Dallas and expected to open in September 2022. The company is currently providing affordable pricing on 100 generic drugs as of January 2022 to treat a variety of conditions including Diabetes Mellitus, asthma and heart conditions via an online service directly to consumers as a cash business. Drug price is being calculated by negotiated cost plus 15% and a pharmacist fee of $3.00 as well as shipping fee of $5.00. Insurance coverage will not apply but the website indicates that many of the drugs listed are less costly than with use of some insurance plans. See list of available meds @ https://costplusdrugs.com/medications/.
The cost of drugs has been an ongoing issue in the USA for many years. Most of the recent publicity has been directed at orphan drug therapy and other exceptionally high cost drugs that are lifesaving yet not affordable to most of the general consumer populations. Perhaps this new venture will prove successful not only for cost saving measures that will make common lifesaving drugs affordable to those in need but also for new ventures that further expand on the mission of access to all. Even a tiny pebble can cause a ripple in a still body of water.
2022 FDA Drug Approvals
The following drugs recently approved by the FDA but are not yet available so pricing information has not been provided for most of them.
Quviviq (Daridorexant) approved on 1/7/2022 for treatment of insomnia.
Cibingo (Abrocitinib) approved on 1/14/2022 for treatment of refractory, moderate to severe atopic dermatitis.
Kimmtrak (Tebentafusp-tebn) approved on 1/25/2022 for treatment of unresectable or metastatic uveal melanoma. One source suggests cost to be $37,520/100mg vial. Dosing initiated with loading doses on day one, day eight and day seven followed by weekly dosing that expected to require use of one vial as ongoing treatment until disease progression or development of unacceptable toxicity. Based on suggested cost, annual treatment could exceed $1.9M.
Bibliography for Clinical Notes – January 2022
https://www.npr.org/2022/01/24/1075344246/mark-cuban-pharmacy
https://www.npr.org/2022/01/24/1075344246/mark-cuban-pharmacy
https://costplusdrugs.com/medications/ list of medications for CostPlus
October 2021 - Clinical Notes
By:
Karen Cunningham | October, 26 2021
Clinical Notes – October 2021
Rocktavian (valoctocogene roxaparvovec) Resubmitted for Approval in EU
In July 2021, BioMarin announced positive results of the GENEr8-1 Phase III clinical trial for adults with severe hemophilia type A receiving Rocktavian gene therapy. The EU had requested study data for an additional year to validate treatment durability demonstrated in earlier but smaller trials. This has led to resubmission of a marketing authorization application (MAA) by BioMarin & validation by the European Medicines Agency (EMA) for accelerated assessment. Initial launch date estimated to be in September 2022 in the EU could achieve earlier approval of the first gene therapy for hemophilia due to corroborative data from the phase III trial.
Previously in August 2020, the FDA had rejected approval for Rocktavian for the same reason as noted by EMA and required a minimum of two years of follow up data from the larger phase III trial. Results from the smaller trials had shown treatment nearly eliminated bleeds in thirteen patients given high doses of Rocktavian, freeing them from taking regular medications to control their disease. However, the FDA concluded that the participants had inadequate follow up time since some data from the phase III trial showed effectiveness of Rocktavian appeared less potent and seemed to wane over time. The last patient in the US trial will complete two years of study in November 2021 with resubmission to the FDA for review expected by mid to late 2022. However, the FDA decision may not be possible before the end of 2021 or in 2022. BioMarin plans to resubmit a biologics license application (BLA) in Q2 of 2022.
Clinical trial results have shown Roctavian to be well tolerated and without new safety concerns. The most common adverse event was high levels of alanine aminotransferase, a liver enzyme that is suggestive of liver damage and common in gene therapies. Twenty-two trial participants reported 43 serious adverse events, all of which have resolved. No clotting related adverse events reported & no patients developed antibodies against factor VIII that could have impact on the effectiveness of treatment.
Administration of Rocktavian is via a single infusion directly into the bloodstream. It uses a modified adeno-associated virus to deliver a functional copy of the F8 gene that provides instructions to the cells in the liver, which is the primary producer of clotting factors in the body. The estimated cost for this gene therapy is still $3M. While other pharmaceutical companies are developing hemophilia gene therapies, estimates indicate that BioMarin will have market share of 30% & global sales of $1B in 2027 due to being the first gene therapy approved for hemophilia.
SerpinPC for Treatment of Hemophilia A and B in Phase 2a Proof of Concept Trial
A new experimental biologic for hemophilia, SerpinPC is in clinical trial and showing high dose treatment safely reduced overall bleed rates up to 88% and spontaneous joint bleeds by up to 94% in adults with severe hemophilia A & B who were not using preventative treatment. Administered via subcutaneous injection, SerpinPC has the potential to treat all types of hemophilia regardless of disease severity or inhibitor status with captivating results that show reduction in bleeds and continued tolerability in both hemophilia A & hemophilia B patients.
SerpinPC is a biologic created by formulation of mutated alpha-1 antitrypsin and serine protease inhibitor developed by Centessa Pharmaceuticals. The mechanism of action is the use of an activated protein C inhibitor designed to restore levels of prothrombinase to allow for increased prothrombin levels in the bloodstream, which assists with production of thrombin that is necessary for clot formation. Phase 2a data shows excellent tolerability & very promising efficacy.
The initial trial was small with only 22 patients enrolled but all of these patients have enrolled in the next trial phase, an open label extension (OLE) study that will focus on a single flat 60mg subcutaneous dose of SerpinPC every four weeks over a period of 48 weeks or 13 total doses. Centessa expects to report study results in the second half of 2022.
Hemophilia A and hemophilia B are X-linked genetic disorders that affect one in 5,000 and one in 20,000 live male births respectively. These diseases can cause spontaneous bleeding that may be life threatening and require acute treatment with large quantities of factor replacement that often results in significant claims in the million dollar range. Many patients are managed with prophylactic therapy on a routine basis individually designed to maintain factor levels to avoid bleeds and can generate high claims although not usually as high as an acute bleed.
Sources:
Bibliography for October 2021 Clinical Notes
https://www.biopharmadive.com/news/fda-rejection-biomarin-gilead-roctavian-filgotinib/583776/
https://www.clinicaltrialsarena.com/comment/biomarins-roctavian-first-gene-therapy-hemophilia-a/
July 2021 - Clinical Notes
By:
Karen Cunningham | July, 12 2021
Clinical Notes – July 2021
Price Shock as FDA Approves Aduhelm to Treat Alzheimer’s Disease
Alzheimer’s disease is a progressive type of dementia that affects memory, thinking and behavior. It affects about 6.2 million people in the USA. Brain cell connections as well as the brain cells themselves degenerate and die resulting in symptoms of dementia. Scientific research has determined the cause of this debilitating condition to be the result of abnormal accumulation of amyloid & tau proteins. Amyloid develops into plaques around the brain & tau deposits form tangles within the brain resulting in symptomology.
There has been a great deal of research to determine how to eliminate and prevent the plaque/tangles within the brain. Unfortunately, none of this research has led to achievement of the goal. Current drug therapy works to restore the balance of neurotransmitters in the brain but these drugs cannot cure the disease although they have shown to improve memory, awareness and function.
Along comes Aduhelm (Aducanumab) developed by Biogen Inc. (a biotechnology company) that has received accelerated approval from the FDA on June 7, 2021. The Alzheimer’s Association lobbied the FDA urging approval stating that even though the drug presents “marginal difference for people who have the devastation of Alzheimer’s to look to.” However, with the announcement of Aduhelm approval the first statement from The Alzheimer’s Association said the price was unacceptable and suggested it “will pose an insurmountable barrier to access” and “further deepen issues of health equity.”
Backtracking a bit to the time when initial trial results were available shows Biogen engaged a committee of independent physicians to monitor their two large clinical trials in March 2019. The committee found that the drug was not working as hoped and determined that continued study was futile leading to a public announcement by Biogen that Aduhelm research was being shelved. Biogen scientists immediately reviewed the trial data again and found hints that the drug was actually effective against Alzheimer’s leading to a plan to convince the FDA to approve the drug.
Biogen established Project Onyx to further their mission along with the assistance of an FDA Director for alleged “off the books” meetings. This led to the suggestion by the FDA to utilize a regulatory shortcut called accelerated approval, granted for drugs that treat a life threatening or serious condition and provides a meaningful therapeutic advantage over existing treatment.
Three members of an expert panel who had recommended the FDA reject the drug have resigned in protest and the former health secretary called for a federal investigation into the FDA’s approval. The approval based on the drug’s ability to clear toxic protein plaques in patients’ brains; a regulatory route that FDA officials had told the advisory committee was not being considered for approval during committee meetings since the trial participants were only those with early onset disease. They further admitted that Ahuhelm had not demonstrated clear clinical benefits in slowing disease progression but argued that by removing plaques, it was reasonable to conclude there would be a clinical benefit to patients.
Some physicians are skeptical of using this drug with so little evidence of improvement in cognition and side effects that include amyloid-related abnormalities in the brain (ARIA,) headache, confusion, dizziness, vision changes & nausea as well as hypersensitivity reactions including angioedema & urticaria. The most common side effects were ARIA, headache, falls, diarrhea, confusion/delirium/ altered mental status/disorientation, and happen to be many of the complications of Alzheimer’s disease that medical treatment attempts to alleviate.
Another surprise was the announcement that annual cost for Aduhelm would be $56K for monthly infusions that would continue for an unknown duration. Biogen defended the cost with the statement; “We believe the price is substantiated by the value it is expected to bring patients, caregivers & society.” They also pointed to lifesaving cancer therapies that can cost nearly three times as much. In the meantime, ICER has evaluated Aduhelm & determined that the drug would only be cost-effective if priced between $3,000 & $8,400. This is due to insufficient evidence that the drug benefits patients. Debate over the cost is active considering that 5.8 million people over age 65 have some form or Alzheimer’s and could be eligible for treatment due to the broad labeling. The US government is particularly concerned since estimated cost to Medicare is $33.5B.
Alzheimer’s can be a devastating diagnosis not only for the individual but also family members who become caregivers. It is easy to understand why these people would look for any type of treatment that delays the symptoms even if it is only short term but with inadequate evidence to support efficacy and potential side effects it may not be the right path to follow.
ZUMA Trial Shows Strong Evidence for Use of Yescarta as Second Line Therapy for Lymphoma
Kite Pharma had projected a 33% improvement in event free survival using Yescarta CAR-T therapy as a second line treatment for Large B Cell Lymphoma (LBCL) when enrolling patients into the Zuma Trial but the results recently released showed 60.2% improvement in event free survival. The study compared current standard treatment for LBCL, consisting of antibody therapy with Rituxan as first line treatment. If disease recurs or the patient is refractory to treatment then a different chemo drug may be administered to induce remission & is referred to as second line or salvage therapy. Patients who respond to this treatment will typically then undergo high dose chemotherapy followed by autologous Stem Cell Transplant.
The goal of the Zuma-7 Trial was to evaluate whether the use of Yescarta is more effective than standard second line therapy for treatment of patients with relapsed/refractory LBCL. Yescarta demonstrated that it could significantly shrink tumors in more patients than standard treatment as well as an observation of a life extension trend. According to the principal investigator for the Zuma-7 trial “Yescarta dramatically improved patients’ outcomes and could make for a potential paradigm shift for LBCL“.
This puts Yescarta in the path of the newly approved Breyanzi that also reported successful treatment for LBCL as second line therapy but had a much smaller trial population than the Yescarta trial. In addition, the Breyanzi data was only an interim analysis as opposed to the two years of trial data analysis reported for Yescarta (approved for treatment of LBCL since late 2017.) Kite Pharma had also received FDA sign off on the trial design upfront, which precludes the need for discussion regarding the validity of the study while the Breyanzi study did not.
What can this mean for patients and insurers? It is hopeful that the competition between the two drugs will result in driving down costs of treatment for LBCL and if CAR-T therapy provides superior results to high dose chemo and stem cell transplant with less side effects then it truly can become a paradigm shift in the fight against lymphoma.
Sources:
Bibliography for July 2021 Clinical Notes
https://www.statnews.com/2021/06/30/calls-investigation-fda-approval-biogen-alzheimers-drug/
https://www.statnews.com/pharmalot/2021/06/30/biogen-alzheimers-icer-medicare-fda/
https://www.statnews.com/pharmalot/2021/06/30/biogen-alzheimers-icer-medicare-fda/
Yescarta/Breyanzi
April 2021 - Clinical Notes
By:
Karen Cunningham | April, 21 2021
Clinical Notes – April 2021
FDA Approves First Cell-based Gene Therapy for Multiple Myeloma
On March 26,2021, Abecma (ide-cel) a new gene therapy developed by a collaborative effort between Bluebird Bio and Bristol Myers Squibb was approved by the FDA for treatment of multiple myeloma that is no longer responsive to four or more previous lines of therapy.
Multiple Myeloma is a cancer that develops from B-lymphocytes in the bone marrow and causes overproduction of plasma cells, a type of white blood cell. Healthy plasma cells help fight infection by making antibodies that recognize and attack germs. These cancerous cells accumulate in the bone marrow and crowd out healthy red and white blood cells and platelets as well as produce abnormal proteins that can cause complications. This can lead to bone destruction and bone marrow failure, damage to the immune system, kidneys and affect the red blood cell count.
Standard treatment has included chemotherapy, stem cell transplant (SCT) and supportive care that may include treatment of bone destruction, pain, anemia, renal failure, fatigue, infections, hypercalcemia and emotional distress. Unfortunately, none of these treatments can cure multiple myeloma and most patients eventually experience relapse as only 3-10% remain in complete remission for more than 10 years.
Abecma is a new chimeric antigen receptor (CAR) T cell therapy and the first agent in its class, genetically engineered to target a protein identified as B-cell maturation antigen (BCMA) found in malignant plasma cells. Once the drug infusion occurs, the re-engineered cells seek out and kill BCMA containing cells. Treatment includes a risk evaluation & mitigation strategy called Abecma REMS due to the risk of cytokine release syndrome or CRS, neurotoxicity, hemophagocytic lymphohistiocytosis or macrophage activation syndrome. The drug package insert contains boxed warnings about these side effects.
Lymphodepletion chemotherapy with Cyclophosphamide and Fludarabine prior to infusion of Abecma is indicated to decrease the number of T, B & NK cells to allow space for newly infused cells. Per an expert at Dana Farber, it is expected that the “450 million cell dose which is the highest and most efficacious will likely be used by academic cancer hospitals where the treatment will be offered.”
Results from the phase II KarMMA trial involving 127 patients with relapsed/refractory myeloma with evaluation of response for 100 of the trial participants. Results showed overall response rate of 72% (combined complete response/partial response) and stringent complete responses (sCR) in 28% of patients. The median time to response was 30 days with duration of response of 11 months for all responders and 19 months for those with complete response.
Administered as a single dose infusion with reported cost of $419,500 per manufacturer. However, there is a high rate of complications particularly due to CRS resulting in lengthy hospital stays for supportive treatment and exceptionally high claims of $1M or more.
Breyanzi Approved for treatment of relapsed/refractory large B-Cell Lymphoma
Breyanzi (Lisocabtagene maraleucel) is another new CAR T cell therapy manufactured by Bristol Myers Squibb and approved by the FDA on February 8, 2021. Designed to treat adults with relapsed or refractory large B-cell lymphoma (R/R LBCL) who have received two or more lines of systemic therapy including diffuse LBCL not otherwise specified, high-grade B-cell lymphoma, primary mediastinal LBCL and follicular lymphoma grade 3B. However, the treatment of Primary Central Nervous System Lymphoma with Breyanzi is not an approved indication.
According to data from the TRANSCEND NHL 001 trial, 192 patients received treatment with Breyanzi. Of those patients, 73% achieved a response and 54% who had minimal or no detectable lymphoma remaining after treatment. Partial response achieved in 19% of the patients. Median duration of response was 16.7 months in all responders. Patients who achieved a complete response did not reach a median duration period. Serious adverse events occurred in 46% of patients and 4% of patients had fatal adverse events.
The FDA requires daily patient monitoring either in person or remotely for the first week after infusion. Patients must also remain within proximity to the infusion facility for at least three more weeks thereafter. Bristol Myers will provide a wearable monitoring device that allows patients to track their temperature.
Treatment may result in complete remission with durable response for many months. Approximately half of the patients in the study above had minimal or no detectable disease after treatment. An additional 19% demonstrated partial response.
Administered as a single dose infusion with prior lymphodepletion chemotherapy. Reported cost per manufacturer is $410,300 but as with other CAR T-cell therapies, there is high risk for complications that could lead to claims of $1M or more.
Recap of Other Gene Therapies Approved by the FDA
1.
Yescarta (Axicabtagene Ciloleucel) approved October 18, 2017 for treatment of adults with certain types of relapsed or refractory large B-cell Lymphoma after receiving two or more lines of systemic therapy and includes Diffuse large-B cell Lymphoma (DLBCL.) Also approved March 5, 2021 for adult patients with relapsed or refractory Follicular Lymphoma after two or more lines of systemic therapy.
2.
Kymriah (Tisgenlecleucel) approved May 1, 2018 for treatment of Acute Lymphoblastic Leukemia (ALL) for patients up to age 25 years of age with B-cell precursor in second or later relapse. Also indicated for treatment of adult patients with relapsed or refractory large B-cell Lymphoma after two or more lines of systemic therapy; includes diffuse large B-cell Lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma and DLBCL arising from Follicular Lymphoma.
3.
Tecartus (Brexucabtagene autoleucel) approved July 24,2020 for treatment of adults with relapsed or refractory Mantle Cell Lymphoma (MCL)
Sources:
https://www.mayoclinic.org/diseases-conditions/multiple-myeloma/symptoms-causes/syc-20353378
https://www.statnews.com/2021/03/26/fda-approves-first-personalized-cell-therapy-for-patients-with-multiple-myeloma/?utm_campaign=pharmalittle&utm_medium=email&_hsmi=118457303&_hsenc=p2ANqtz--DzqE6O7bqXPmqeMseGkMaAEQDYbU4hzgduuORsFuO8PzPHmrSoMNEOe1vfVIFHLL-L_uiRAU8ZAGqIBdZ3VzAL658gM3rRr35qbr-5mMlIcCPchM&utm_content=118457303&utm_source=hs_email
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878535/#:~:text=In%20addition%20to%20chemotherapy%2C%20prophylaxis,therapeutic%20management%20of%20myeloma%20patients.
https://www.fda.gov/media/147055/download#page=2
https://www.cancerhealth.com/article/fda-approves-new-cart-therapy-multiple-myeloma
https://www.biopharmadive.com/news/bristol-myers-liso-cel-fda-approval-car-t/594660/
https://scrip.pharmaintelligence.informa.com/SC143786/Breyanzi-Is-Third-To-Market-But-BMSs-First-CART-Therapy-Priced-Above-Competitors#:~:text=Breyanzi's%20list%20price%20is%20%24410%2C300
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel
By: Karen Cunningham | January, 18 2021
Pemazyre (Pemigatinib) is the first FDA approved treatment for adults with specific types of previously treated advanced cholangiocarcinoma, a rare form of cancer that forms in the bile ducts. Pemazyre 13.5mg/day is administered on days 1-14 every 21 days until disease progression or development of toxicity. The overall response rate was 36% with 2.8% having a complete response and 33% having partial response with 63% of patients who responded to treatment had duration of 6 months and longer. An additional 18% had a response lasting 12 months or longer. The most common side effects were hypophosphatemia, anthralgia, stomatitis, hyponatremia, abdominal pain and fatigue. Reported annual cost for Pemazyre is $312K-$636K depending upon discount.
Zeposia (Ozanimod) is approved for treatment of adults with relapsing forms of multiple sclerosis (RMS) including clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease. It is the first SP1 receptor modulator that does not require patients to have a genetic test before starting the drug or have to be observed after receiving their first dose. Zeposia is administered orally on a daily basis w/starting dose on days 1 and 4 of 0.23mg daily, and then on days 5 and 7 the dose of 0.46mg daily followed by maintenance dose of 0.92mg daily on day 8 and thereafter. It has shown a 48% lower rate of clinical relapses at 1 year and 38% lower rate at 2 years compared with intramuscular Inteferon beta-a1 (the current first line treatment for RMS.) The drug also reduced the size and number of brain lesions more than Interferon beta-1a. The drug may cause a transient decrease in heart rate and delays in atrioventricular conduction so advice to physicians is to titrate the dose to reach maintenance level. Reported cost is $85K-$190K annually depending upon discount.
Tepezza (Teprotumumab-trbw) is approved for treatment of thyroid eye disease in adults. Grave’s ophthalmopathy or thyroid eye disease is a rare and potentially vision-threatening autoimmune disease that manifests in patients with thyroid disease. Tissue inflammation behind the eye causes the eyes to push forward & bulge outward. Tepezza 10mg/kg as a starting dose is administered followed by 20mg/kg once every 3 weeks for a total of 8 cycles. The most common side effects were muscle spasm, nausea, alopecia, diarrhea, fatigue, hyperglycemia, hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Reported cost for this treatment is $370K-$731K depending upon discount.
Nurtec ODT (Imegepant) is approved for acute treatment of migraine in adults. The drug is a calcitonin gene-related peptide (CGRP) receptor antagonist. CGRP is thought to be the root cause of migraines. 21% of patients given Nurtec ODT had pain relief after 2 hours of taking the drug. Further studies have shown that it may also help prevent migraines as researchers discovered patients taking one dose of Nurtec every other day had 4.5 fewer monthly migraine days/month. Nurtec 75mg is administered orally as a single dose with maximum of 75mg per 24 hours. Reported AWP cost is $127.50 per 75mg tablet.
https://www.nasa.gov/feature/nasa-and-telemedicine
https://www.fiercehealthcare.com/tech/7-predictions-for-how-technology-will-shape-healthcare-2021
https://www.fiercehealthcare.com/tech/trump-administration-to-invest-8m-broadband-for-rural-telehealth-access
https://www.fiercehealthcare.com/tech/jpm2021-teladoc-projects-2020-revenue-to-reach-1-1b-as-it-expands-virtual-primary-care
https://www.fiercehealthcare.com/tech/doctor-demand-study-finds-covid-19-telehealth-surge-driven-by-behavioral-health-chronic
https://www.fiercehealthcare.com/tech/fcc-chief-unveils-200m-program-to-boost-telehealth-services-amid-covid-outbreak-0
https://newsroom.clevelandclinic.org/2020/10/06/cleveland-clinic-unveils-top-10-medical-innovations-for-2021/
https://www.mdlinx.com/article/7-new-fda-approved-drugs-in-2020/7gBf1HvDxmEXqUNqoXT5wR
By: Karen Cunningham | November, 12 2020
https://medcitynews.com/2020/01/these-drugs-have-patents-expected-to-expire-in-2020-and-some-will-face-generic-competitors/
https://www.healthcaretechoutlook.com/news/4-ways-ai-will-impact-healthcare-nid-2057.html?utm_source=Newsletter&utm_medium=email&utm_campaign=healthcaretechoutlook_weekly
By: Karen Cunningham | July, 2 2020
As reported in November 2019, researchers at the University of Nottingham in the UK have discovered tumor associated antigens or TAA’s that are good indicators of cancer and have further identified panels of TAA’s known to be associated with breast cancer. The new blood test looks for autoantibodies against these specific TAA’s in blood specimens taken from the patient. Although additional research and validation will be required, the researchers estimated that this test may become available within four to five years. A test such as this would allow for very early intervention to implement disease prophylaxis and intervene before the disease process has reached advanced stages which are more difficult to treat and usually have a poor prognosis.
https://www.breastcancer.org/symptoms/testing/types/blood_marker
https://www.sciencedaily.com/releases/2019/11/191103125418.htm
It is known that the same medication given in the same dose can affect people very differently as evidenced by the onset of side effects in some individuals and none in others. Pharmacogenetic testing looks at specific genes to determine the types and dosages of medication as well as whether serious side effects would be expected in the individual patient. This information is then utilized during the decision making process regarding which drug would be the most beneficial to treat a particular diagnosis in the individual patient, essentially adopting a drug regimen designed specifically for that patient
Upon completion of another clinical trial; Phase3 Titan study, Erleada achieved FDA approval in September 2019 for treatment of metastatic castration resistant prostate cancer or mCRPC also in combination with androgen deprivation therapy as statistics showed significant overall survival and radiographic progression-free survival. The cost for Erleada 240mg which is administered daily can run from about $150K -$330K annually for both types of prostate cancer.
https://www.janssen.com/erleadar-apalutamide-significantly-improved-overall-survival-patients-non-metastatic-castration
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In this article, MRM's nurses share their recent front line experience in acute care settings. Opening remarks by our lead clinician - Karen Cunningham.
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COVID-19 has caused a major global impact very quickly and will continue to cause disruption in our daily lives for an undetermined length of time. This pandemic has demonstrated how fragile our lives can be when a new disease is encountered for which there is no available testing or effective treatment to prevent the continued attack.
These last several weeks have demonstrated our complacence with disease prevention and our lack of preparedness to approach a pandemic situation. We have been given a great deal of information about COVID-19 that at times is contradictory, frustrating and confusing.
We are very fortunate to have a healthcare system that employs dedicated, knowledgeable and compassionate first responders and caregivers to provide treatment and comfort to those who have contracted this virus. We would like to share three accounts from members of MRM's Clinical team who wrote about their experiences working in acute care during this pandemic. Two NICU nurses and a cardiac nurse share their stories:
NICU Nurse
It is a very surreal time to be a nurse working in the hospital. I am a NICU nurse at a large Children’s Hospital. The NICU is typically referred to as the “sterile unit” but in the past few weeks that feeling has changed greatly. We started out with staff having to wear a level one surgical mask during our shift and a pair of goggles, which we were given and told we would only receive one pair so they needed to be cleaned and stored in our locker after each shift. We have our temperature taken when we enter the hospital and given a ticket to give to our manager upon arrival to our unit/floor. We are currently still given one surgical mask a day that we are to store in a brown paper bag when we take it off for breaks and then throw away at the end of our shift. Visitation restrictions also took affect a few weeks ago, which have resulted in only the parents (or the 2 people with the baby band) being allowed to visit. Their temperature is also taken when they enter the hospital and they are asked a series of screening questions.
About 2 weeks ago, we started to have all visitors in the hospital wear a mask. The only visitors allowed in our hospital are parents of pediatric patients and one visitor for a patient at the end of their life. Visitors able to wear a homemade mask or are given a homemade mask at the front desk once they check in. They are told to take it home with them each day and wash it. Parents are very nervous for their babies and often times hesitant to even hold them because of the risks. We have had some parents state they are not coming to visit because of their concern of risking any exposure to their baby.
When we attend deliveries we have to wear an N95 and then our surgical mask that we have for the day over it. The only people who are given an N95 are the NICU team attending deliveries and if you are taking care of a rule-out or COVID positive baby. We currently have 3 babies in isolation due to their moms being positive for COVID. We test the babies at day 1, 3, and 7 of life, although this practice seems to be changing frequently. We have gone from not testing babies of COVID positive moms unless the baby is symptomatic to doing serial testing on them. The COVID positive mom is not allowed to visit her baby and neither is her partner, so these babies are not allowed to have any visitors. We have had 2 moms critically ill and in the ICU. N95 masks are kept locked in managements office and you are only handed one if your assignment falls under the criteria to wear one. It is mandatory for men to be clean shaven each day because our hospital does not have PAPRs (powered air-purifying respirator) available. Face shields are available for people who wear glasses but they must keep the one they are originally given and wear it each shift they work.
The mood in the hospital has become more solemn and everyone recognizes the seriousness of the situation. I often hear coworkers expressing their personal concerns of working in the hospital and risk of exposure being brought home to their families and children. At our hospital now, if you are exposed (to a positive patient prior to them testing positive) and not wearing the proper PPE during exposure you are to continue to work and are not being tested unless you develop symptoms. In the beginning, if this scenario occurred you were to not work for 2 weeks and tested if symptoms develop.
Staffing shortages became a much larger issue due to this so the current guidelines in our hospital changed to continuing to work unless you become symptomatic. We recently received an email from management stating that we can be deployed to any unit/floor in the hospital if staffing needs necessitate this coverage. I have been a NICU nurse for the past 14 years and not taken care of an adult patient since nursing school. I am also pregnant and due in 4 weeks so the thought of having to go to an adult floor is nerve-racking. Our NICU census has remained high so I do not anticipate this happening in the near future to our staff but the possibility is there. My husband who is a NICU/PICU/Pediatric Respiratory Therapist has been recently floated to the adult ICU and adult ER due to the needs in the adult units. This is a very unsettling time for all, but healthcare workers continue to do what is asked of them and the resilience that healthcare workers possess has become more evident during this pandemic.
Cardiac Nurse
This pandemic has impacted our lives in many different ways. As nurses we knew we would be on the front-line in the battle against coronavirus. I worked on a cardiovascular procedure unit which consisted mostly of elective cases. After our first coronavirus huddle, I knew the “normal” routine of my day was going to change drastically. The reactions of my fellow nurses varied greatly. Some were ready to take on new roles during this crisis and others unsure about taking the risk of contracting the virus and potentially giving it to family members. Much like other hospitals, we have nurses in different phases of their life. Nurses that are pregnant and/or have young children at home, nurses that have spouses with autoimmune diseases and others planning on retiring within the year.
Having handed in my resignation before COVID-19 had impacted us, as my final days approached and the world changed dramatically, I had a lot of mixed emotions about leaving my good friends and co-workers at the hospital. I think about not being there to support the team I’ve been working with since 2002 and I wonder how the new nurses that I recently trained were coping with all the change along with being a new nurse. In some ways I felt guilty that I didn’t stick with the team and stay by their side to fight coronavirus and help out during these crazy times on the front-line. In other ways I’m slightly relieved. Thankfully in my state, the number of cases have so far been much lower than predicted. However, models are predicting we have not seen the worse, I’m hoping we won’t.
NICU Nurse
The current environment in the hospitals, here in the Southeast seems to be more of watchful waiting and planning for a storm. I work in multiple neonatal intensive care units around the city. Since this setting houses the most vulnerable and immuno-compromised population of patients, limiting visitors and limiting exposure policies are always in place. Constant hand-washing and vigilant foaming with hand sanitizers is our foundational practice. N-95 masks are rarely reserved for healthcare workers in this area, due to low likelihood of exposure. The day of my N-95 mask testing, I became a bit concerned that the hospital did not have appropriate sized masks for many of us in their inventory. It was slightly disconcerting, to know that I could be called to deliveries for patients who were COVID-19 positive. I have to say that our department leadership stepped up quickly, recognizing that this unregulated exposure would compromise the safety of a whole unit full of NICU babies. We quickly gathered an existing task-group and channeled our efforts to define practice roles with tiered exposure approach. We ran daily simulation drills to identify and correct safety issues.
In the NICU, I feel that I am in my safe zone. Outside of NICU is a different world where we must constantly maintain a higher level of vigilance. We are always listening to the constant muttering about “that COVID patient next door.” Despite that, much good has resulted from this conflict. Small and large local businesses as well as individuals are stepping forward to provide support and safety equipment. Our processes in healthcare management are being fine-tuned and our use of resources is becoming more efficient. The once, paper and pencil driven world of healthcare, is now utilizing technology more efficiently. However, all of this, does not come without its challenges. It is true that the 0-17 pediatric population make up only a small percentage of COVID+ patients, but that number is not ZERO. Therefore, the role of parents, caring for their own children is becoming limited and our fortitude and desire to provide family-centered care is being tested by families who cannot visit their babies.
MRM salutes all the first-responders who are keeping us safe 24/7 and going above and beyond the call of duty!
MRM has setup a resource page on our website where we'll track useful information for the stop loss industry.
What’s New?
A recent study by Good Rx reported by Fierce Pharma resulted in development of a list of the most expensive drugs for 2020. Drugs appear in descending order from highest to lowest monthly cost. Reported pricing is before rebates or discounts and reflects only the drug cost not administration fees that often lead to significantly higher claims. Here are the top 10:
1. Myalept - Indicated for treatment of Lipodystrophy; a rare disorder that affects how the body stores & uses fat. Reported cost is $71,306/month and annual claims of $926,978.
2. Ravicti – Indicated for treatment of urea cycle and ornithine deficiency; an enzyme deficiency that impacts waste removal after digestion. Reported cost of $55,341/month and annual claims of $719,433
3. Mavenclad – Indicated for treatment of Acute Myeloid Leukemia, Hairy cell Leukemia & Mantle cell Lymphoma. This drug was FDA approved in 2019 for relapsing remitting Multiple Sclerosis. This drug is administered over a period of two years with two cycles/year then discontinued for at least two years. Reported cost of $53,703/dose. This drug is administered for two cycles each year resulting in annual claims of $214,812.
4. Actimmune – Indicated for treatment of chronic granulomatous disease & malignant osteoporosis. Reported cost of $52,777 resulting in annual claims of $633,324.
5. Oxervate – Indicated for treatment of neurotrophic keratitis; a corneal disease and is administered 6 times/day daily at two hour intervals for eight weeks. Reported cost is $48,948 or annual cost of $97,896.
6. Takhzyro – Indicated for prophylactic treatment of hereditary angioedema (HAE.) Reported cost is $45,464 and annual claims of $545,604.
7. Daraprim – An antimalarial drug indicated for the treatment of isoporiasis in HIV infected patients, pneumocystic pneumonia in HIV infected patients and for toxoplasmosis. Reported cost is $45,000 and annual cost of $585,000.
8. Juxtabid – Indicated for treatment of homozygous familial hypercholesterolemia; a severe inherited disorder which causes abnormal lipid metabolism. Reported cost is $44,714 or annual cost of $544,215 annually.
9. Cinryze – Indicated for prophylactic treatment of hereditary angioedema (HAE.) Reported cost $44,141 and annual cost of $573,833.
https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Other-Factor-Deficiencies/Factor-XIIIhttps://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Other-Factor-Deficiencies/Factor-XIII
https://www.fiercepharma.com/pharma/20-most-expensive-pharmacy-drugs-u-s-2020?mkt_tok=eyJpIjoiWVdZeE9UTmxOR0l3WlRFNCIsInQiOiIwUnp3M1hPWTMxNFZqbjBKWmREdWNoSFFLZ1BVb3V5VEpnY2VJXC9obTZQMlRRYzZTMjNOdzRmXC9TNVdaK3FqY00wRTlPUDdJVnlPUDFQMGV1TVFWdDN2UHVCcWR3MXlWNjJQeXBwZk5uMERWd1IyYVd3YXRPenY1eEVUZkIzY2Z5In0%3D&mrkid=3239073
https://www.hemophilia.org/Bleeding-Disorders/Future-Therapies
https://www.payingforcures.org/
https://hemophilianewstoday.com/2019/01/28/cell-therapy-long-term-treatment-hemophilia/
https://stemcellres.biomedcentral.com/articles/10.1186/s13287-019-1138-8
https://www.hemophilia.org/Newsroom/Industry-News/Sigilon-Releases-Study-Data-on-Hemophilia-Cell-Therapy
https://www.usnews.com/news/health-news/articles/2020-01-02/gene-therapy-may-be-long-term-cure-for-type-of-hemophilia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058236/
https://ghr.nlm.nih.gov/condition/cystinosis
https://www.spinraza.com/en_us/home/taking/how-spinraza-works.html
https://www.clinicaltrialsarena.com/projects/zolgensma/
https://smanewstoday.com/avxs-101-avexis
https://www.payingforcures.org/research-and-tools/
https://www.medtronic.com/us-en/healthcare-professionals/products/cardiac-rhythm/infection-control/tyrx-antibacterial-envelope.html
https://www.medscape.com/viewarticle/910530
https://www.nejm.org/doi/pdf/10.1056/NEJMoa1901111
https://www.medtronic.com/us-en/healthcare-professionals/products/cardiac-rhythm/infection-control/tyrx-antibacterial-envelope/clinical-outcomes.html
Expected to be FDA approved in May 2019, this drug designed to treat spinal muscular atrophy (SMA) caused by a defect in the SMN1 gene which makes a protein critical to survival of motor neurons and is a one-time therapy meant to replace that gene. Price benchmarks set by ICER (Institute for Clinical and Economic Review) for Zolgensma once in a lifetime administration for infantile-onset Type 1 population is $310K – $900K. Similar to Spinraza also indicated for treatment of SMA but available for treatment of both children and adults has current list price of$750K for the initial year & $375k per year thereafter. Projected sales for 2024 are $1.43B.
What’s New - There were four new chemotherapy medications approved by the FDA this past November and they all come with high price tags.
Spinraza (Nusinersen) has received approval by the FDA in December 2016 and is indicated for the treatment of spinal muscular atrophy or SMA. The drug cost will be $125,000 per injection and resulting in claims of $750,000 for the first year and $375,000 every year thereafter on a lifelong basis. AWP is $150,000/dose.
SMA is a rare disease affecting about 35,000 patients worldwide. It is a progressive brain disorder that destroys motor function. Prior to the development of Spinraza, there were limited treatment options and mostly supportive care as there is no mechanism available to alter the genetic mutation that causes the disease. The lifespan of children diagnosed with SMA varies widely with some succumbing at an early age and some living into adulthood.
We have already reviewed some presale cases in 2017 that had members diagnosed with SMA and likely to begin treatment with Spinraza. This exceptionally high initial cost and subsequent annual costs will have a significant impact for our Stoploss policyholders, particularly those with low deductibles. This will make identification of patients with this disease paramount to underwriting so that sufficient premium can be collected or perhaps result in declination of a case due to high risk.
Exondys (Eteplirsen) has received FDA approval in September 2016 and is indicated for the treatment of Duchenne Muscular Dystrophy in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication was approved under an accelerated approval process based on an increase in dystrophin in skeletal muscle observed in some patients treated with Exondys 51. A clinical benefit of Exondys 51 has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.
The dosage is weight based; 30mg/kg once weekly to be administered via intravenous infusion over 35-60 minutes. AWP pricing for 500mg/10ml is $9,600 and for 100mg/2ml pricing is $1,920. The company has set a weight based price of $300,000/year for a 25kg (55lbs) patient. Average weight for American Female is 166 lbs or 75kg & average weight for American Male is 196 lbs or 89 kg.
Dupixent2 is a new biologic drug developed to treat eczema. It was approved by the FDA on March 28, 2017 for treatment of adults with moderate to severe atopic dermatitis or eczema that isn’t controlled with topical treatments. It is given via subcutaneous injection twice a month.
Clinical trials have shown the Dupixent is at least as effective as Cyclosporine and more effective than phototherapy in controlling atopic dermatitis. It is safer than Cyclosporine and phototherapy. The annual cost for this drug is $37,000.
