#1 Gene Therapy for Hemoglobinopathies

#1 Gene Therapy for Hemoglobinopathies

For those living with conditions with no known cure, the anxiety and anger can be too much to bear. Wanting and waiting for a solution to make symptoms and side effects disappear, sick patients everywhere continue to suffer. Gene therapies have made the seeming miracle a reality for some, using most advanced precision medicine to alter cells for the treatment of disease. Scientists and researchers have agreed – it’s hemoglobinopathies’ turn.

Hemoglobinopathies are genetic disorders affecting the structure or production of the hemoglobin molecule – hemoglobin being the red protein responsible for transporting oxygen in the blood. Produced by the beta-globin gene, hemoglobin disorders arise when this gene is dysfunctional. The most common hemoglobinopathies include sickle cell disease and thalassemia – combined affecting over 330,000 kids born worldwide every year. Hispanic-Americans and Black or African-American populations are at an increased risk for hemoglobinopathies, often carrying the inheritable trait. One out of every 365 Black or African-American births is affected by SCD. While sickle cell disease causes misshapen hemoglobin molecules, thalassemia disorder is the presence of less hemoglobin than normal. Both deprive the body of sufficient blood and oxygen, which damages nerves and organs, including the kidneys, liver, and spleen, and can be fatal. 

A blood and bone marrow transplant from a Human Leukocyte Antigen (HLA) matched sibling is currently the only cure for sickle cell disease, and only a small number of people are able and eligible to have said transplant. There are treatments that can reduce symptoms and prolong life, effective to a certain extent. Thalassemia is managed (in severe cases) through frequent blood transfusions. More mild cases are often prescribed a supplemental B vitamin, known as folic acid, to help treat anemia. Folic acid can help red blood cells develop, but treatment with folic acid is usually done in addition to other therapies. But for those unresponsive to these treatments, and even those doing their best with existing symptom management, the obvious lack of cure is devastating. 

Latest research in the hemoglobinopathy space has brought an experimental gene therapy for those suffering from sickle cell disease and thalassemia. Adding functional copies of a modified form of the beta-globin gene into a patient's own hematopoietic stem cells, the gene therapy gives patients the potential to make functional hemoglobin molecules, thus functional red blood cells. With the goal of reducing the presence of sickled red blood cells, hemolysis, and other complications, this new therapy represents the first-ever gene therapy for either of these conditions. 

There are several ongoing trials exploring the therapy’s use in both sickle cell disease and thalassemia. Data released in June 2019 from the company’s ongoing Phase I/II study show robust production of gene therapy-derived anti-sickling hemoglobin. In the study, patients with six or more months of follow-up after treatment for sickle cell disease had median sickle hemoglobin levels reduced to 50% or less of total hemoglobin in the absence of blood transfusions. In thalassemia, data from Phase I/II Northstar studies of the therapy found sufficient hemoglobin production to reduce or eliminate the need for transfusion support among patients with thalassemia who would otherwise require chronic blood transfusions.

These results earned the therapy breakthrough designation from the FDA. In both indications, the therapy has either moved into Phase III or Phase II/III clinical trials with Conditional Marketing Authorization in the EU for the thalassemia indication.
Utilizing some of the greatest precision science to date, medical researchers are nearing an approved gene therapy to cure these chronic blood disorders – a Top 10 Medical Innovation if there ever was one. 

#2 Novel Drug for Primary-Progressive Multiple Sclerosis

#2 Novel Drug for Primary-Progressive Multiple Sclerosis

While sudden onset of a condition is terrifying for patients and their loved ones, gradual onset, too, brings fear by way of worsening symptoms and slow loss of the individual they were before defined by disease. Such is the devastating case for those diagnosed with primary-progressive multiple sclerosis (PPMS) – a disabling disease of the central nervous system.
In individuals with multiple sclerosis (MS), the immune system attacks the fatty protective myelin sheath that covers their nerve fibers – causing communication problems between the brain and the rest of the body. The disease can result in permanent damage or deterioration of the nerves and eventual death. Most people with MS are diagnosed between the ages of 20 and 50, with at least two to three times more women than men coming down with the disease. It isn't completely clear why MS develops in some people and not others. A combination of genetics and environmental factors appears to be responsible.

Most people, nearly 85% of those with MS, have a relapsing-remitting disease course. They experience periods of new symptoms or relapses that develop over days or weeks and usually improve partially or entirely. These relapses are followed by quiet periods of disease remission that can last months or even years. At least 50% of those with relapsing-remitting MS eventually develop a steady progression of symptoms, with or without periods of remission, within 10 to 20 years from disease onset. This is known as secondary-progressive MS. Approximately 15% of people with MS experience a gradual onset and steady progression of signs and symptoms without any relapses – the subset of MS known as primary-progressive.

There are more than a dozen disease-modifying therapies approved by the FDA to treat MS, but these compounds are only indicated for the most common relapsing-remitting course. Historically, there's been very little doctors could do for their patients with PPMS other than provide medications and other therapies to treat noticeable symptoms – nothing slowed the progression of the disease itself. But a novel therapeutic monoclonal antibody approved in March 2017 represents a different scientific approach to treating PPMS. The drug targets a type of immune cell called CD20-positive B cell that plays a key role in the disease. Given once every six months by an intravenous (IV) infusion, ocrelizumab is the first and only MS treatment to target these specialized cells and treat the primary-progressive population.

Positive results from a Phase III study of the drug showed significantly slower disability progression over a median treatment duration of three years when compared to placebo – patients were 24% less likely to have disability progression for 3 months. Separate analysis of the same study showed greater patient satisfaction after one year with the treatment. More than 120,000 people have been treated with ocrelizumab globally, and data continue to show a consistent and favorable benefit-risk profile in clinical trial and real-world settings.

Other novel work in the MS space includes the recent FDA approval of a drug with a similar method of action. Also targeting the CD20 protein found on the surface of B-cells, ofatumumab became the first MS therapy approved for at-home administration. The FDA ruled on ofatumumab in August 2020. But ocrelizumab remains the only FDA-approved medication for the struggling subset of MS patients with the primary-progressive condition. As a novel treatment made available to a population for which none existed, ocrelizumab is a Top 10 Medical Innovation for 2021.

#3 Smartphone-Connected Pacemaker Devices

#3 Smartphone-Connected Pacemaker Devices

In our increasingly connected world, it may come as no surprise to learn that patients are leveraging technology to become more engaged in their treatment plans and are reaping the benefits of improved outcomes. Consumers have the ability to track data from blood-glucose levels to steps taken and now, even the data transmitted by their implantable cardiac devices.

Implantable devices like pacemakers and defibrillators are medical devices that generate electrical impulses delivered by electrodes to cause the heart muscle chambers to contract and therefore pump blood to the body. They are also used to prevent or correct an arrhythmia – a heartbeat that is uneven, too slow, or too fast. The pacemaker can be thought of as the steady hand guiding your heart through each day, while the defibrillator is the guardian angel standing ready to keep you safe if your heartbeat becomes dangerously irregular or stops. Pacemakers and defibrillators can be implanted for a variety of reasons, but are commonly used in patients with arrhythmia, both slow and fast, or heart failure. Though millions of patients have pacemakers and defibrillators, many lack a basic understanding of the device they have or how it functions.

Earning its place amid other new innovative medical technology are Bluetooth-enabled pacemaker devices to remedy this issue of disconnection between patients and their cardiac treatment. Used in conjunction with a mobile app, these connected devices are allowing patients greater insight into the data their doctor sees. The tech provides patients information related to transmission success history, battery longevity, vital tracking, and physical activity as well as access to device information (implant date, model number, etc.), FAQs, a symptom journal to share during in-office visits, and other educational resources. Designed to securely and wirelessly send device data to the patient’s network via smart technology, the connected pacemakers and their smartphone application eliminate the need for a dedicated bedside monitor or other remote monitoring hardware. Patients, therefore, benefit from increased freedom, knowing that their pacemaker can connect with their clinic from their mobile device wherever they may be.

Wireless pacemaker transmission has been a theme in cardiac care for several years, but has always involved additional monitoring equipment that usually resides in the patient’s bedroom and transmits data to the secured network for a physician to review. Patients have had no visibility into the process and no access to the data from their device. For the first time, pacemakers have the ability to communicate securely and directly with the technology that patients use every day like smartphones and tablets. This interaction brings the benefits of remote monitoring seamlessly into patients' lives, potentially leading to enhanced and more efficient patient engagement with their physicians. The easy access to information is changing the way patients track, understand, and take interest in their heart health.

Results published May 2020 from a study of the technology demonstrated that patients who used the mobile app to which the pacemaker transmits were more likely to adhere to their pacemaker remote monitoring schedule than patients who used traditional bedside monitors. The study found that patients using the technology successfully completed 94.6% of scheduled transmissions, which was superior to all three bedside monitor control groups (whose results ranged from 56.3% to 87.1%).

Keeping cardiac patients engaged and informed, new smartphone-connected pacemakers and their mobile tracking apps are bringing patients into the care equation. With less in-person visits in this time of social distance, the connectedness this innovation brings is significant. But its implications go beyond COVID-19 as clinicians continue to leverage state-of-the-art technology to provide the most advanced care.

#4 New Medication for Cystic Fibrosis

#4 New Medication for Cystic Fibrosis

Passing a hereditary disease to a child is one of a parent’s worst fears. Virtually uncontrollable, there are a variety of inherited conditions that affect children the minute they’re born. For the one in every 35 Americans who carry a defective cystic fibrosis (CF) gene, this concept of inheritance is a grim reality.

People with CF have inherited two copies – one from each parent – of the defective CF gene, containing a slight abnormality called a mutation. Though most genetic tests screen for defective CF gene mutations, there are approximately 2,000 known of the disease, and tests often miss those more obscure DNA alterations. Thus, the disease can be passed unknowingly in any number of the approximate 1,000 new cases of CF diagnosed each year. Today, more than 30,000 people in the US are living with CF, with more than 75% of cases confirmed by age two.

With CF, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the CFTR protein to become dysfunctional. When the CFTR protein is not working correctly, it’s unable to help move chloride to the surface of cells in the body. Without the chloride to attract water to the surface, the mucus in various organs becomes thick and sticky.
In the lungs, the mucus clogs the airways and traps germs, leading to infections, inflammation, respiratory failure, and other complications. In the pancreas, the buildup of mucus prevents the release of digestive enzymes that help the body absorb food and key nutrients, resulting in malnutrition and poor growth. In the liver, the thick mucus can block the bile duct, causing liver disease. Each day, people with CF complete a combination of treatments including airway clearance to help loosen and get rid of thick mucus, inhaled medications to fight infections and keep the airways clean, pancreatic enzyme supplement capsules to improve absorption of vital nutrients, and CFTR modulators.

CFTR modulators are a class of drugs designed to correct the malfunctioning protein made by the CFTR gene. There are several CFTR modulators on the market. Still, the medications developed prior to last year had only been effective in people with highly specific mutations, rendering a great amount of individuals ineligible for treatment. In October 2019, the FDA approved the first triple combination therapy to treat patients with the most common CF mutation – F508del.

Elexacaftor/tezacaftor/ivacaftor is a fixed-dose combination medication of CFTR modulators and chloride channel openers approved for use in those patients with CF who have at least one F508del mutation in the CFTR gene. F508del is estimated to represent 90% of individuals living with CF in the U.S.

The new combination drug helps the CFTR protein function more effectively – thinning the mucus in the affected organs. The efficacy of the new drug in patients with CF aged 12 years and older was demonstrated in two trials. The first trial was a 24-week, randomized, double-blind, placebo-controlled trial in 403 patients with an F508del mutation and a second minimal function mutation that results in little or no chloride channel activity. The second trial was a four-week, randomized, double-blind, active-controlled trial in 107 patients with two F508del mutations. In each trial, primary analysis explored increases in the percent predicted forced expiratory volume in one second (ppFEV1) – an established marker of cystic fibrosis lung disease progression. The newly approved medication increased ppFEV1 in both trials – 13.8% and 10%, respectively.

Tremendous advancements in specialized CF care have added years and quality of life to the lives of people with the condition. There have been dramatic improvements from the first half of the 20th century when a child with CF rarely lived long enough to attend elementary school. Today, many are realizing their dreams of attending college, pursuing careers, getting married, and/or having kids. Pipelines remain full of potential treatments, including RNA therapies, for people with rare and nonsense mutations or those for whom current medicines show no improvement. There’s undoubtedly more CF innovation to come, riding on the coattails of elexacaftor/tezacaftor/ivacaftor approval.

#5 Universal Hepatitis C Treatment

#5 Universal Hepatitis C Treatment

While news of a pandemic captured headlines in 2020, the US continues to battle silent epidemics in population health – opioid use and hepatitis C, to name a few. Given its ‘silent epidemic’ classification by the CDC, hepatitis C has emerged as a major public health issue in the United States. More than 3.2 million Americans are infected according to the CDC, yet as many as 75% are not aware that they carry the virus. The number of acute hepatitis C cases reported in the population more than tripled between 2010 and 2016, and more deaths are attributed to hepatitis C than from all 60 other reported infectious diseases combined.

Hepatitis means inflammation of the liver. When the liver is inflamed or damaged, its function can be affected. Heavy alcohol use, toxins, some medications, and certain medical conditions can all cause hepatitis. However, hepatitis is often caused by a virus. In the United States, the most common hepatitis viruses are hepatitis A, B, and C. The liver infections caused by these three viruses can show similar symptoms, but they affect the liver and are spread in different ways. Hepatitis A is usually a short-term infection, while hepatitis B and C are more likely to remain in the body and cause chronic infection. There are vaccines to prevent hepatitis A and hepatitis B, but there is no vaccine for hepatitis C.

Hepatitis C is spread through contact with blood from an infected person. Today, most people become infected with the hepatitis C virus by sharing needles or other equipment used to prepare and inject drugs. Chronic hepatitis C can result in serious, even life-threatening health problems like liver failure, cirrhosis, and liver cancer. People with chronic hepatitis C often have no symptoms and don’t feel sick, but when symptoms appear, they often are a sign of advanced liver disease.

There are at least six distinct hepatitis C genotypes, or strains, which are genetically different groups of the virus. Knowing the genotype helps inform treatment recommendations and the duration of treatment for those seeking it. Approximately 75% of Americans with hepatitis C have genotype 1, 20-25% have genotypes 2 or 3, and a small number of patients are infected with genotypes 4, 5, or 6. Before a few years ago, existing hepatitis C treatments were either accompanied by adverse side effects, or only effective for certain genotypes of the disease. In 2016, new medication brought widespread treatment opportunity via the ability to treat all six major genotypes of the disease.

Sofosbuvir/velpatasvir, a fixed-dose combination medication, was approved as the most applicable regimen for the treatment of hepatitis C in adults. More than 90% effective for hepatitis C genotypes one through six, the medication inhibits proteins that play a key role in hepatitis C RNA replication. With the therapy, most people take just one pill, once a day for 12 weeks.

Results from Phase III clinical trials of the medication demonstrated that 95 to 99% of patients who received the novel treatment had no virus detected in the blood 12 weeks after finishing the course – suggesting the patients’ infections had been cured. The approval of the combination therapy saw follow-on innovation in the subsequent approval of two other medications to treat all six genotypes of hepatitis C: glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilapresvir. The drug’s approval, prescription, and pace-setting ability have allowed an effective treatment option for a wider scope of patients with the disease. A Top 10 Medical Innovation for 2021, universal hepatitis C treatment is helping community clinicians combat this silent epidemic.

#6 Bubble CPAP for Increased Lung Function in Premature Babies

#6 Bubble CPAP for Increased Lung Function in Premature Babies

Underweight and frail, babies born prematurely are susceptible to a host of issues. While equally as precious as their full-term counterparts, these early deliveries often require specialized care upon arrival – including ventilation for those with infant respiratory distress syndrome (IRDS).

For IRDS, infants are commonly administered surfactant – medication to lower surface tension – during mechanical ventilation. Although treating IRDS with surfactant improves clinical outcomes, mechanical ventilation can cause lasting lung injury in preterm infants and contribute to the development of chronic lung disease and other devastating conditions like reactive airway diseases and neurodevelopmental delay as the child grows. The incidence of CLD differs significantly among institutions, but after adjusting for centers’ distributions of birth weight, race, and sex, the lowest incidence of CLD in literature has been reported from centers that use the method of bubble CPAP (b-CPAP) as early as possible. Administering b-CPAP rather than surfactant and mechanical ventilation in the delivery room and as the primary mode for respiratory support of all premature infants in respiratory distress is an important advancement in the world of neonatology.

Unlike mechanical ventilation, b-CPAP is a non-invasive ventilation strategy. It is a method by which continuous positive airway pressure is delivered to a spontaneously breathing newborn to maintain lung volumes during exhalation. In b-CPAP, blended and humidified oxygen is delivered via infant-sized prongs, and pressure in the circuit is maintained by immersing the end of the expiratory tubing in water. The depth to which the tubing is immersed underwater determines the pressure generated in the airways of the infant. As the gas flows through the system, it “bubbles” out and prevents buildup of excess pressures.

The oscillating, rather than constant, pressure provided by b-CPAP plays a role in its safety and efficacy of volume retention in an infant’s lungs. Its physiologic advantages include optimally matched blood and airflow in the lungs, increased functional residual lung capacity, and maintenance of inflation of alveoli – the functional unit of lung tissue. Compared with mechanical ventilation and tracheal intubation, b-CPAP minimizes physical and subsequent biotrauma and induces a favorable strain that stimulates lung growth when administered over a prolonged period. Other advantages over mechanical ventilation include lower cost, ease of application by nursing staff, and lower risk of complications. The method has also been proposed as an inexpensive method of delivering ventilation in developing countries.

In a center with historical 33% CLD development in its population of very low birth weight (VLBW) infants, the implementation of a b-CPAP program was associated with CLD reduction to 6%. The reduction of CLD rates does not occur immediately – it requires significant time to develop staff experience and achieve the full effect of b-CPAP integration into the ventilation workflow. In a follow-up study of the same institution, the consistency of outcomes was demonstrated over 12 years with an even further reduced CLD rate of 5%.

While neonatologists have been exploring with b-CPAP usage for years, its widespread adoption has only just begun, with large children’s hospitals and specialized centers switching to use of this method alone. New research has confirmed its place within premature infant ventilation, given its CLD-reducing capabilities. Allowing for the growth of strong children with lungs full of life, b-CPAP earned its Top 10 spot for 2021.

#7 Increased Access to Telemedicine through Novel Practice & Policy Changes

#7 Increased Access to Telemedicine through Novel Practice & Policy Changes

Extending the healthcare environment into the patient’s home has been a goal for decades. The reasons have been obvious – removing the geographic barriers to care can result in timelier, more efficient, and more optimal outcomes – but the movement has been slow. COVID-19 saw increased adoption of telemedical practices as clinicians were forced to conduct their visits online. This practice opened the door to increased consumer adoption and an increasingly virtual care model through shifts in policy.

By increasing access to physicians and specialists, telehealth helps to ensure that patients receive the right care at the right place and at the right time. Telehealth expands access to services that otherwise may not be sustained locally. However, there are several barriers to expanding access to care through the use of telehealth, including risks like the uncertain and dynamic regulatory environment, exposure to potential medical malpractice, data breaches, licensure issues, and statutory restrictions on how Medicare covers and pays for telehealth.

Through the years, policies have slowly shifted to expand coverage of virtual care, but many geographic areas and services that are safe to provide via telehealth had yet to be explored. In response to COVID-19, on March 6, Congress passed the Coronavirus Preparedness and Response Supplemental Appropriations Act – a legislation to allow physicians and other healthcare professionals to bill Medicare fee-for-service for patient care delivered by telehealth during the public health emergency. Since then, state and federal regulators have moved quickly to reduce telehealth adoption barriers, understanding that these new tools could speed access to care while protecting healthcare workers and community members.

The CMS launched several emergency initiatives that expanded Medicare and Medicaid coverage, including increasing the types of providers able to use telehealth, allowing providers more freedom to use different modalities, and expanding the number of sites qualifying for coverage. State regulators added their own emergency directives, expanding Medicaid coverage, enabling more care providers to use telehealth, requiring private payers to cover telehealth services and, in some cases, tweaking the rules to allow out-of-state providers to use telehealth to treat residents, and providers in the state to treat residents of other states. Other federal agencies took action as well. The HHS dished out a number of grants and awards, while the Federal Communications Commission (FCC) launched its own $100 million COVID-19 Telehealth Program, aiming to support broadband expansion projects that pushed new telehealth services into rural areas where connectivity is lacking.

These measures opened the floodgates for telehealth, allowing for new programs and the expansion of existing networks. In April 2020, a survey of some 1,300 physicians found that 90% were using at least some form of telehealth, and 60% were planning to continue that practice after the emergency. In May 2020, a survey of hospitals and health system executives put that number at 63%, well above the 20% adoption rates seen prior to the pandemic. At Cleveland Clinic, use of virtual visits rose across specialties, transforming the model of delivery nearly overnight.

Technically, there is a ceiling for the utilization of telehealth. Not everything can be addressed over video, and long-term regulation remains fuzzy, but there are still immense growth opportunities as use-cases continue expanding and adoption ramps. With the fire lit by COVID-19, the health ecosystem has been primed for success by way of expedited outcomes, improved patient/provider experience, and increased access to care.

#8 Vacuum-Induced Uterine Tamponade Device for Postpartum Hemorrhage

#8 Vacuum-Induced Uterine Tamponade Device for Postpartum Hemorrhage

Postpartum hemorrhage (PPH), a devastating complication of childbirth, might feel like a problem for our ancestors, but the complication remains unpredictable and continues to occur worldwide. And though modern medicine has developed treatments that have reduced death rates and disabilities, many of these are limited to developed societies.

Characterized as excessive bleeding after having a baby, PPH affects anywhere from one to five in 100 women who give birth (1 to 5%). Several studies on PPH have revealed a disproportionate effect on the child-bearing population – Black, Hispanic, Pacific Islander, and Asian women are known for an increased risk. Those in less developed areas of the world are at heightened risk as well, but be Sub-Saharan Africa or New York City; no woman is immune to this complication.

If the uterus does not contract strongly enough after delivery of a baby and the placenta (postpartum), the blood vessels in the area where the placenta was attached remain open, leading to continued bleeding/hemorrhage due to uterine atony (failure to contract). Uterine atony is the most common cause for PPH. The aim of treatment for PPH is to find and stop the cause of the bleeding as quickly as possible. Mothers experiencing PPH may require blood transfusions, drugs which may cause dangerous side effects, long uncomfortable procedures, and even emergency hysterectomy with loss of fertility. Non-surgically, the use of a balloon to compress bleeding inside the uterus is popular. Known as uterine balloon tamponade, this method has a high success rate for PPH and has been used for some time. But the newest advancement in this space is that of vacuum-induced uterine tamponade.

More physiological than uterine balloon tamponade, which applies outward pressure to the inside of the uterine wall distending the uterine cavity, vacuum-induced tamponade involves negative pressure created inside the uterus causing the cavity to collapse. A device comprised of a teardrop-shaped, soft silicone ring is placed into the uterus, where gentle suction causes it to contract and shrink in size – compressing the blood vessels so bleeding stops. The contraction motion achieved with the vacuum suction is natural to the body and mimics that of contraction after successful child birth. The vacuum-induced device represents another minimally-invasive tool for clinicians as they battle the frightening complication. It also provides a low tech solution that is potentially translatable to developing countries with low resource availability.

Many startup companies have created investigational devices, but there are a few that have fully developed products to treat PPH. In a clinical trial of one such company’s product, hemorrhage was controlled within 2 minutes, with no recurrence and very little blood loss after treatment initiation in all women involved. The company ran a follow-on clinical study involving fifteen leading US hospitals to fully evaluate the safety and effectiveness of the system. Data from this trial is being gathered to support an application for US FDA marketing clearance – the study was completed in July 2020.

A new method still finding its place in the OB workflow, vacuum-induced uterine tamponade is another innovation ensuring PPH is a thing of the past and that families in waiting rooms across the globe hear, “mom and baby are doing great.”

#9 PARP Inhibitors for Prostate Cancer

#9 PARP Inhibitors for Prostate Cancer

About one man in nine will be diagnosed with prostate cancer in his lifetime. While optimism and progress in the last ten years have brought solace to some, the disease remains the second leading cause of cancer death among men in the US.

Treatment for prostate cancer typically depends on the stage. While some types of prostate cancer grow slowly – requiring little more than monitoring for changes or improvement – others are more aggressive and demand action in the form of radiation, surgery, hormone therapy, chemotherapy, or other treatments. Metastatic, castrate-resistant prostate cancer (mCRPC) is an incurable form of prostate cancer that continues to grow even when the amount of testosterone in the body is reduced to very low levels. Researchers are constantly looking for new treatment options for mCRPC and other refractory forms of prostate cancer.

PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP-ribose polymerase (PARP). They are drugs developed for multiple indications, including the treatment of heritable cancers. In women with ovarian and breast cancer with specific genomic defects (BRCA1 or BRCA2 positive mutations), PARP inhibitors have shown success and received approval as a targeted cancer therapy. While first-line cancer DNA-creating proteins in the body are often dismantled by chemotherapy, BRCA genes have a built-in backup up plan to repair cancer DNA. Repair is carried out by PARP proteins. Inhibiting said PARPs, therefore, causes cancer cell death. As approximately one in four men with prostate cancer appear to have similar genomic defects, the class of drugs began a journey of exploration in prostate cancer years ago.

The PARP inhibitors rucaparib and olaparib have been demonstrated to delay the progression of prostate cancer in men with refractory cancer and BRCA mutations. Both were approved for the prostate cancer indication in May of 2020. Olaparib’s approval was based on results of the Phase III PROfound trial, which showed a statistically-significant and clinically-meaningful improvement in the primary endpoint of radiographic progression-free survival (rPFS) versus standard antiandrogen hormone therapies. Specifically, olaparib reduced the risk of disease progression or death by 66% and improved rPFS by 7.4 months compared to the 3.6 months of the comparison treatment. The FDA approval for rucaparib was based on data from the multi-center, single arm TRITON2 Phase II clinical trial. Rucaparib produced a 44% overall response rate and achieved a 55% PSA response rate – rates associated with better rPFS and overall survival (OS).

While prostate cancer continues to affect the lives of nearly 200,000 men per year in the US, the emergence of PARP inhibitors for this indication represents an enormous advancement for the disease. A handful of additional clinical trials exploring other PARP inhibitor compounds and their use in prostate cancer are ongoing – some exploring combination with other therapies. The approval of rucaparib and olaparib has opened the door to a world of therapeutic options and survival possibility for men around the world.

#10 Immunologics for Migraine Prophylaxis

#10 Immunologics for Migraine Prophylaxis

Your head is throbbing, you’re nauseous, and even the dimmest light from across the room feels like you’re staring directly into the sun. You haven’t moved for hours, were forced to call off work, and have canceled your evening plans. You have another migraine – and it’s your fifth this month.

A migraine is more than the occasional pressure headache. It’s a neurovascular disorder associated with dysfunction of the cerebral nerve cells and blood vessels that affects more than 38 million people in the US – an estimated 12% of the adult population. In short, migraines are dysfunctional reactions in the brain, causing excessive relaxation or dilation of cranial blood vessels. These dilated blood vessels then mechanically activate sensory fibers from the trigeminal nerve located in the vessel wall, which convey pain impulses to the brainstem and other higher brain centers. Migraines are most likely to occur in women between the ages of 15 and 55, but the impact on quality of life is universal to those who suffer. Roughly 90% of individuals with migraine difficulties report missing work or failing to function normally during a migraine attack. For a third or more of those with migraine, financial security is a concern, and about a quarter worry they will lose their job due to their symptoms. The Migraine Research Foundation estimates that US employees take 113 million sick days per year due to migraines, creating an annual loss of $13 B. The cost to patients is great as well, incurring 70% higher healthcare-related costs than those without the disease.

For pain relief at the first sign of an oncoming migraine, there are several types of medication. Over-the-counter pain relievers are popular, as are ergot alkaloids, triptans, and, to a lesser extent, prescription opioids. While effective at treating individual headaches, they do not provide preventative treatment and are not considered a cure. Additionally, the drugs don’t work for everyone and share the unpleasant side effect of increasing headache frequency and severity with use. Prevention of migraines is the more current area of research. For some time, multi-purpose drugs like blood pressure medications, antidepressants, anti-seizure drugs, and botox injections have been used to prevent attacks. Not developed specifically for migraine, these methods are met with mixed results.

In 2018, new medications arrived on the scene to help head off migraine pain. Known as calcitonin gene-related peptide monoclonal antibodies, a type of immunologic, these compounds were designed specifically for migraine prophylaxis. The class of drugs works by blocking the activity of a molecule called calcitonin gene-related peptide (CGRP), which spikes when pain impulses are sent from the trigeminal nerve to the brain. When CGRP is released, it causes intense inflammation in the meninges, the membrane coverings of the brain, and causes the pain of a migraine attack. The first three medications in this class approved for the prevention of both chronic and episodic migraines are erenumab, galcanezumab, and fremanezumab. Either acting as agonists for the CGRP receptor or GCRP protein, these medications were approved by the FDA in May and September of 2018, respectively. The treatments are given as once-monthly injections and are extremely well-tolerated. For most people, there are few adverse reactions aside from some pain at the injection site.

For a report published in July 2018, the Institute for Clinical and Economic Review (ICER) reviewed nearly 20 clinical trials of CGRP inhibitors for preventing both chronic and episodic migraines. The ICER found that, overall, migraine patients who took CGRP inhibitors had greater reductions in headache days per month versus other preventive medications. Higher odds of 50% response and greater reductions in days using acute medication per month were reported for all the interventions versus placebo. In short, all three FDA-approved CGRP inhibitors, as well as eptinezumab, the first-ever intravenous migraine prophylactic approved in February 2020, have earned an important spot in the arsenal of medications that prevent migraines.

Actively prescribed in 2020 with no signs of slowing adoption in 2021, this new FDA-approved class of medication for migraine sufferers is helping countless individuals reclaim their personal and professional lives.