Every year in the United States, approximately 700 women die due to pregnancy or childbirth-related causes, according to the CDC-and that’s despite the fact that 17 cents of every dollar is spent on healthcare, according to 

 from the Organization for Economic Cooperation and Development.

This and other pressing healthcare challenges-such as the need to encourage appropriate adoption of new treatments including immunotherapy-mean the industry is ripe for creative thinking and innovation, says 

Editorial Advisor Don Hall, principal of DeltaSigma LLC, a consulting practice specializing in strategic problem solving for managed care organizations.

“We have to start finding innovators in our business,” he says. “We have to start creating innovative cultures, because the opposite is really what we have in our industry. [Healthcare] cultures tend to be very conservative-and focused on reducing risk.”  

Here are four recommendations from Hall and other experts regarding how you can spark creative programs and solutions at your organization.

Julie Coffman, a partner at consulting firm Bain & Company, recommends forming a leadership cadre that carries forth changes ushered in by innovative researchers and physicians. Coffman cites the example of a young physician-researcher with a breakthrough therapy that he’s working hard to get the facility to embrace. Enabling the physician-researcher’s success starts with connecting him to individuals who can help move the project up the chain, she says. Make sure your organization has a system in place to encourage this type of partnership between individuals and leadership who have already demonstrated the ability to encourage organizational adoption of innovation, says Coffman. “The key to effective change management, in lots of ways, is developing the early victories, being able to talk about them, and celebrating them with the right people that carry a lot of sway in the organization-and then allow the cascade to naturally be pulled, as opposed to pushing it on people who might be resistant to change their behavior without feeling the need,” she says.

Consult frontline employees who work one-on-one with customers.

Hall laments that far too many employees are never asked for insight on improving the customer experience-and that means their valuable ideas never arrive in the executive suite.

Focus on empowerment, not accountability. 

At many organizations, prioritizing accountability has become a key management philosophy, says Joe Tye, CEO and head coach at Values Coach training and consulting firm. He says that tends to discourage employees from taking creative approaches to solving problems. While Tye, who previously served as chief operating officer at The Toledo Hospital in Ohio and Baystate Medical Center in Worcester, Massachusetts, admits that managers must be held accountable for budgets and nurses must be held accountable for the care they provide to patients, he insists that using only “carrots and sticks” to hold people accountable isn’t going to encourage them to solve problems creatively. “When leaders clearly define expectations for what I call the ‘Invisible Architecture’ of core values, organizational culture, and workplace attitudes, they rarely have to hold people accountable hierarchically with carrots and sticks because it’s accomplished through the peer pressure of cultural accountability,” says Tye.

Use insight from customers to drive more enlightened decision making

“No one is calling an insurance company to compliment them,” says Hall. “Nobody is calling to say, ‘I love this product.’ They’re telling you about a problem they’re having.” Whether customers are looking for more online access to providers or quicker access to lab results and treatment recommendations, those problems need to be addressed in the executive suite, he says.

Articles

This first article in our new leadership series explores how managed care executives can cultivate smart ideas and stay ahead of the competition.

Four Ways to Spur Innovation at Your Managed Care Organization

The cost to treat cancer in the United States could reach $156 billion in 2020, according to the National Cancer Institute. And innovative medications have a significant impact on the cost of care.

To illustrate the growth of new therapies, Jacob Chaffee, PharmD, clinical pharmacist for emerging therapies at Blue Cross Blue Shield of Michigan, noted during his presentation at the Academy of Managed Care Pharmacy Managed Care and Specialty Pharmacy (AMCP) Annual Meeting, in Boston April 25, that more than 45 novel cancer therapies have been approved by the FDA since 2013. And more than 600 molecules are in a late-stage pipeline.

According to Chaffee, two milestones for novel cancer treatment include FDA’s approval in August 2017 of the first CAR-T therapy, Kymriah (tisagenlecleucel), for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia. In October 2017, the federal agency approved a second CAR-T therapy, Yescarta (axicabtagene ciloleucel), for the treatment of adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment.

Chaffee defined some of the terms used in novel cancer treatment, including:

, where a patient’s immune cells are reengineered, and returned to their body. The cells, in turn, expand and serve as “living drugs” to recognize and target tumor cells. These cells can remain within the patient’s body for months after the infusion, which can lead to long-term remission.

, which is also referred to as CRISPR-Cas9, targets specific stretches of DNA for editing using programmable systems. In this process, genes in living cells can be modified or corrected in the treatment of genetic causes of disease or to improve current therapies to treat cancer, muscular dystrophy, and HIV and other infectious diseases. (According to the International Society for Stem Cell Research, using CRISPR/Cas9 together with CAR-T therapy may improve the engineering of T cells where they carry multiple therapeutic features for either increasing specificity or suppressing side effects, or both. Further, the risk of inserting the CAR gene in inappropriate locations can be reduced through the use of CRISPR/Cas9.)

Payers’ primary concerns with CAR-T therapy


Chaffee noted that payers are particularly concerned with the following when it comes to CAR-T therapy:

He then broke down the total cost of care associated with CAR T, which can range from $523,000 to $795,000 per case. The breakdown of those costs includes:

Drug cost, which can range from $373,000 to $475,000

Administration and monitoring, which can range from $50,000 to $120,000

Adverse events, which can range from $100,000 to $200,000

To illustrate a possible model for payment of treatments such as CAR T, Chaffee's colleague, Christina Link, PharmD, a clinical manager for the payer’s specialty pharmacy utilization management team, then shared the following results of moving the site of care to community oncology centers when providing patients with novel cancer treatments:

$8,000 decrease in medical costs per patient per month

18% reduction in emergency department visits at 10 days

28% reduction in emergency department visits in 72 hours

Top Cost Considerations for CAR-T, CRISPR Cancer Treatment 

Payers are stepping up efforts to manage the cost and utilization of orphan drug treatments.

That’s according to Steven Jung, PharmD, BCPS, drug information pharmacist at San Diego’s MedImpact Healthcare Systems, who discussed the topic at the Academy of Managed Care Pharmacy Managed Care and Specialty Pharmacy (AMCP) Annual Meeting, in Boston April 25.

The FDA’s orphan drug designation program provides orphan status to drugs and biologicals that are defined as appropriate for the treatment, diagnosis, or prevention of rare diseases and disorders that fit the following criteria:

Affecting fewer than 200,000 people in the United States

Affecting more 200,000 people but aren’t expected to recoup the costs of developing and marketing the treatments

Organizations that sponsor the development of orphan drugs can take part in incentive programs, such as tax credits for clinical trial costs, relief from prescription drug user fees, and marketing exclusivity eligibility upon FDA approval.
Jung pointed out the growth in orphan drug approvals by the FDA has increased from fewer than 30 in 2013 to 70 in 2017.

Because of a backlog in reviewing orphan drug applications, the federal agency launched the “90 in 90 Plan,” which means it will respond to all requests within 90 days, while maintaining consistent, scientifically rigorous review of such applications.

In addition, Jung said the FDA issued draft guidance to the pharmaceutical industry in December 2017 that it would no longer grant orphan drug status to pediatric subpopulations if the following conditions weren’t met:

The disease in the pediatric population is a valid orphan subset and the drug meets all other criteria for orphan designation.

The disease in the pediatric subpopulation is a different disease from the disease in the adult population.

How payers are responding to growing costs


Payer sensitivity to the cost of orphan drugs continues to rise, according to Jung. That’s because these treatments can cost hundreds of thousands of dollars each year per patient. In addition, new treatments and indications are being approved by the FDA, and there are few, or in some cases, no available treatment alternatives.

In response, payers have undertaken benefit design changes to manage both utilization and the cost associated with these treatments, he said. These changes include:

Formulary restriction and specialty tiers

Presenting the results of his analysis of reimbursement data, Jung also noted that payers put more coverage restrictions-the most utilized method was prior authorization-on orphan drugs than they do for non-orphan drugs.

Prior authorization criteria typically include the following:

Baseline data, such as genetic screening and laboratory values

Renewal criteria, such as documentation of response

Quantity limit, such as appropriate dosing


Jung’s colleague, Christina Bui, PharmD, a drug information pharmacist, discussed the use of Spinraza (nusinersen), an orphan drug for spinal muscular atrophy, a rare, autosomal recessive neuromuscular disorder where patients experience degeneration of motor neurons of the spinal cord; this results in severe and progressive atrophy of skeletal muscles and generalized weakness. Further, patients experience poor weight gain with growth failure, restrictive lung disease, scoliosis, joint contractures, and sleep difficulties. There are currently two clinical trials underway for Spinraza where patients have achieved positive results, she said. The cost for the first year on Spinraza is $900,000, which includes six doses, and $450,000 in subsequent years for three doses.

Bui also highlighted the use of Brineura (cerliponase alfa) as an orphan drug to treat ceroid lipofuscinosis type 2 (CLN2), an ultra-rare condition that results in rapid deterioration in cognitive and motor functions, and Radicava (edaravone) to treat amyotrophic lateral scoliosis (ALS), which affects 16,000 people in the United States.

How Payers are Responding to Growing Orphan Drug Costs

Some of the most amazing things are happening in the delivery of medical care these days. Surgical techniques, new devices, drugs, and diagnostics can treat and cure many medical conditions. Now the only challenge is who pays for these advances and how. More than ever, managed care pharmacy is at the center of healthcare and needs to help design, develop, and implement new solutions to address this challenge.

, discusses the changing nature of managed care pharmacy and the role it needs to take in curbing healthcare costs. Here are some of my thoughts.

With the growth of specialty pharmaceuticals, the roles of the physician, pharmacist, and patient need to be redefined and the total cost of care must be evaluated to see what really adds value in medical care. We need to develop new models of care to address the new world of healthcare.  

The administrative costs of medical and pharmacy benefits must decrease and there must be more price transparency as patients begin to act as consumers.

Currently, purchasers measure the effectiveness of PBMs by whether they reduce the unit cost of prescription drugs. Utilization management is also widely used to make sure the right drugs are used by the right patients. Systems and processes for this work are driving physicians and pharmacists crazy.

We need to merge pharmacy claims data with medical claims data and patient reported outcomes to measure drug performance and have value-based contracting.

Managed care pharmacy needs to reinvent itself to make value-based contracting happen on the healthcare financing side.

It’s encouraging to see that most industry leaders agree that value-based contracting is a top priority. When asked, “What is the biggest opportunity to reduce specialty pharmaceutical costs?” The most popular response among healthcare executives who took our Managed Care Pharmacy Survey 2018 was value-based contracting (see page X). Further, 60% of respondents said value-based contracting with manufacturers is the best coverage strategy for new, innovative therapeutics and biologics. 

It’s also good to see that new players and new technology to deliver healthcare, such as telemedicine, are continuing to grow. The kitchen countertop in the patient’s home is where the action will happen. New technology from Google, Amazon, and others will drive this change.

As younger patients view time and space differently from senior citizens, the roles of physicians and pharmacists will change and the movement of information will be digital. Pharmacist house calls will be used to provide patient supportive care and lead to more collaboration between physician, pharmacist, and patient.

The use of companion diagnostics to drive personalized medicine will become the standard of care for certain diseases.

Lastly the use of data, analytics, and reporting will drive decision making for physicians, pharmacists, and patients in the delivery and financing of healthcare to ensure the best use of resources.

Exciting times are ahead, and managed care pharmacy is well positioned to drive the necessary changes.

 editorial advisor and chief executive officer of The Pharmacy Group and the TPG family of companies, which provides services to associations, healthcare and information technology organizations, payers and pharmaceutical companies.

Managed Care Pharmacy’s Future: What Health Execs Should Know 

Some patients with life-threatening diseases will now be able to receive experimental treatments without receiving approval for their use from the FDA first.  That’s because President Trump, on May 30, signed the Right-to-Try Act into law. The signing came shortly after the House passed the legislation May 22. The Senate passed the legislation in August 2017.  Under the legislation, patients can access experimental treatments if they are unable to participate in any clinical trial involving an investigational drug and if they have exhausted all other approved treatment options. The bill requires that any unapproved drug must have an active application and not be subject to clinical hold. In addition, the government may not use a clinical outcome associated with use under the legislation to delay or adversely affect a product’s review or approval, unless it is critical to determining its safety or the sponsor requests use of the outcome. Proponents and critics, who we spoke to prior to the president’s actions, have a lot to say about the potential effects.

Under the FDA’s Expanded Access Program, patients under certain circumstances can take experiential drugs that have not yet been FDA approved; however, the FDA must sanction their use. The agency says it approves 99% of the more than 1,000 annual requests for experimental drugs requested through the program.

Starlee Coleman, senior policy advisor, Goldwater Institute, says the FDA is the ultimate arbiter of which drugs should be made available. Still, she believes that the FDA approval requirement under the Expanded Access Program is too time consuming (it requires doctor/patient application to the FDA for a single patient investigational new drug treatment and approval from an independent review board), especially for terminal patients.

“We don’t think Americans should have to apply to the government to save their lives,” she says. “The government shouldn’t be able to say ‘no’ if a manufacturer and doctor approve. Right to Try provides access to potentially life-saving treatment for patients without other options who cannot get into a trial.”

Coleman says drugs available through Right to Try have passed phase 1 trials and continue to be tested, making them safe enough for terminal patients while offering possible benefits. “Right to Try could be particularly beneficial if a trial ends with positive results, but a drug has not yet been approved,” she says. 

She also emphasizes that Right to Try is voluntary for patients, doctors, and manufacturers.

“The most virulent opponents of federal Right-to-Try legislation say that it is not significantly different from expanded use but is simply part of an effort to reduce the regulatory scope of the FDA and the federal government in general,” says Harold Bishop, senior legal analyst, Health Law Group, Wolters Kluwer, a global information company.

Other criticisms, according to Bishop include:

Lack of FDA involvement could reduce safety because information regarding a product’s use, based on confidential information and clinical trial data the FDA holds, would not be available.

Right to Try could drive patients away from clinical trials if they could obtain investigational drugs without participation, thus, narrowing trial population and data accrued though trials.

Without FDA input, unapproved medical products may do more harm than good (under expanded use, the FDA determines that there is sufficient evidence of the safety and potential effectiveness of an investigational product to support its use in a particular circumstance).

The process might divert resources from ongoing clinical trials, resulting in a delay of FDA approval of a product.

Simplification of FDA’s Expanded Access Program has already reduced the time it takes for a treating physician to complete a request from eight hours to 45 minutes, according to the FDA.

Limited supplies of a drug might only be available during a clinical trial process, making requests costly and burdensome.

Arthur Caplan, director, Division of Medical Ethics, New York University’s Langone Medical Center, says proponents of Right to Try believe the drug approval process is long and slow and if a patient is dying, there is no time for patients to enter a clinical trial because they might not qualify if they are too sick.

He isn’t convinced, however, that the FDA is preventing patient access to experimental drugs, as proponents assert. “It’s drug manufacturers who decide who gets a drug, but instead of doing anything to help persuade companies to make their products available to patients, which is the key for access, they (proponents) set their sights on the FDA and accuse it of keeping patients from promising experimental medicines,” Caplan wrote in a recent 

Amy K. Dow, member of law firm Epstein Becker Green, agrees. “Proponents of Right-to-Try legislation seem to overlook the fact that the FDA is not, in general, a significant barrier to access to products. Rather, it approves the vast majority of expanded access requests it receives,” says Dow.

The efforts by supporters of Right-to-Try legislation to remove FDA from the process of providing patients with access to investigational therapies eliminates an important element of oversight provided by the agency but is unlikely to significantly impact the number of patients obtaining access to these products, she adds.

She says limitations on supplies of investigational products and burdens imposed on manufacturers in responding to drug requests are not addressed by the legislation.

Under Expanded Access and Right to Try, manufacturers may choose whether to make an investigational drug available. Brookings, a public policy organization based in Washington, D.C., suggests that drug manufacturers are hesitant to provide preapproval access because of a limited supply-only enough available for a clinical trial-and if a patient suffers adverse effects after taking a drug, that might deter other patients from participation in clinical trials or from purchasing the product after FDA approval.
	
	The Pharmaceutical Researchers and Manufacturers of America, a trade group representing pharma companies, has not taken a formal position on Right-to-Try at press time. Still it has created criteria for determining when to grant access to an experimental treatment outside of a clinical trial, including if a patient has a serious or life-threatening illness and is ineligible for, or otherwise unable to participate in, a clinical trial.

Legislation removes FDA involvement when patients seek experimental medications. Here’s what critics and proponents say.

Right to Try Pros and Cons  

The International Rare Diseases Research Consortium hopes to develop 200 new drugs for rare diseases by 2020, and it seems as if things are better than on track. The FDA granted 77 orphan drug approvals last year and granted 476 orphan drug designation requests, according to law firm Hyman, Phelps & McNamara. Costs for these orphan drugs are skyrocketing.

As these drugs come to market, David Calabrese, RPh, MHP, 

 editorial advisor and OptumRx’s senior vice president and chief pharmacy officer, discusses ways to stabilize economics, access, and appropriate use.

MHE: What can be done to balance economic efficiency with proper access and appropriate use?

: I see four key areas that must be addressed. First, the evaluation of the clinical evidence and projected financial impact must be conducted in as robust and proactive a manner as possible. Ideally, pharmacy and therapeutics committees should be conducting these assessments prior to FDA approval to most effectively protect clients and their members from undo financial burden and safety risk. 

Secondly, utilization management programs must be designed in as comprehensive and academically rigorous a fashion as possible to limit usage to those patients most appropriate for such therapy.  

Third, once patients initiate therapy, close monitoring and care management support is essential to ensure maximal adherence, achievement of therapeutic goals, and that benefits obtained outweigh any unforeseen safety/tolerability issues. 

Finally, population-based analytics will be critical to assess both short- and long-term real-world outcomes for those receiving these therapies.  This will ensure clinical protocols and support mechanisms can be enhanced and refined to optimize clinical and financial benefits.

Which new drugs categories in the near-term pipeline will have the most significant impact on pharmacy cost trends over the next three to five years?

: Newer options for the treatment and prevention of migraines and cluster headaches (CGRP antagonists) will be long-awaited additions to the options available for helping to manage migraine frequency and severity in this rather sizable patient cohort. As a result, uptake has the potential to be rapid and substantial. 

Several drugs are also in late-stage development for treatment of nonalcoholic steatohepatitis

This class is of key significance as there are no FDA-approved treatment options and an estimated 16 million U.S. adults with this condition.

There are numerous drugs, primarily biologic, that are in development for the treatment of Alzheimer’s disease. These include drugs in novel classes like the BACE inhibitors and RAGE antagonists. With the aging of the population, increased prevalence of disease, and limited array of effective treatment options, these drugs also hold the potential for significant market penetration should clinical data prove positive.

How can pharmacy benefit management best change to become more holistic and integrated in focus and function?

:  This will require major industry transformation encompassing, but not be limited to:

Enhanced data integration (medical, pharmacy, lab, EHR, behavioral health, and social determinants of health);

Advanced analytic support including real-world evidence assessment, predictive analytics, and machine learning; 

Progressive, consumer-focused digital resources and engagement vehicles;

Point-of-service provider engagement tools fully-integrated into daily work flow;

Newer formulary and utilization management models that de-emphasize rebates and promote greatest value;

Reformed business models that deliver optimal transparency in all clinical, operational, and financial offerings; and

Greater alignment with target clinical and financial goals between PBMs and clients. 

Tracey Walker is Content Manager for Managed Healthcare Executive. 

How to Rein in Skyrocketing Orphan Drug Costs 

Preparing for pharmacy policy changes can help your managed care organization stay ahead of the competition. Here, pharmacy experts highlight three areas to watch closely. 

Through this federal program, which started in 1992, pharmaceutical companies participating in Medicaid agree to provide outpatient 

 to covered entities at significantly reduced prices. Hospitals and clinics that participate in the program must apply for eligibility and meet specific requirements, says John M. Lonie, RPh, EdD, associate professor of social and administrative sciences at Long Island University – College of Pharmacy in Brooklyn, NY. “The 

 enables covered entities to stretch federal resources and provide more comprehensive services.”

Over the past few years, the 340B program has grown because of policy changes that increased opportunities for purchasing drugs at discounted rates and because eligible entities became more aware of the program, says Emily Cook, MSPH, JD, partner, McDermott Will & Emery, an international law firm.

The program’s growth, however, has led to scrutiny from Congress, drug manufacturers, and other stakeholders. “Among the expressed concerns are that the program is not governed by clear rules, making it difficult to hold participating providers and drug manufacturers accountable for compliance with program requirements,” Cook says. For example, drugs purchased by providers through the 340B program cannot also be eligible for Medicaid discounts, and drug manufacturers must accurately calculate 340B prices. In addition, a lack of data reporting requirements makes it difficult to review and analyze purchases and use of drugs purchased at the discounted rates, she says.

managing director, Dacarba LLC, a professional services firm, points to recurring questions regarding the program’s eligibility rules and whether they are restrictive enough and concerns about the lack of transparency around how savings are used. 

Cook expects a lot of legislative activity in the 340B space this year. Though no new legislation has been passed at press time, five bills have been introduced since mid-2017 and additional bills are coming, she says. To date, the bills have primarily focused on additional oversight and data reporting requirements for participating hospitals. Future bills will likely address which patients can receive discounted 340B drugs from eligible entities, the arrangements for dispensing drugs, and the prices that hospitals can charge patients for these drugs, she says.

Pharmacists and the patient care services they provide are not included in certain sections of the Social Security Act, which determines eligibility for healthcare programs such as Medicare Part B, according to the American Pharmacist Association. The omission limits Medicare beneficiary  access to pharmacist services in the outpatient setting.

“If pharmacists were designated as providers under Medicare Part B, private health plans could no longer use this as a reason to exclude pharmacists as providers,” says Fernando Gonzalez, RPh, MS, assistant professor of pharmaceutical sciences at Long Island University – College of Pharmacy. “Pharmacists are now on the verge of obtaining provider status as a result of many states pushing for this status. The federal government will have the ultimate decision. Once the federal government grants provider status, states will follow suit.”

Pharmacist status would give them the ability to bill for services such as medication management, and receive payment from Medicare, Medicaid, and other private payers, Gonzalez says.

Provider status is closely linked to scope of practice. In some states, pharmacists could be given the same authority to provide services to Medicare patients as nurse practitioners and physician assistants. These services might include continuing therapy, which involves monitoring drug levels, side effects, adverse reactions, and compliance, as well as ordering diagnostic tests to evaluate patient disease parameters, such as blood levels of narrow therapeutic index drugs. “Pharmacists’ ability to bill for nontraditional pharmacy services such as ordering diagnostic tests for checking cholesterol or ordering tests to check blood levels of drugs like warfarin could positively impact healthcare executives’ bottom line, maximizing therapeutic outcomes that will reduce hospitalizations and changes in courses of therapy,” Gonzalez says. “Therefore, they should be aware of the impact that pharmacists as providers can bring to their organizations.”

The Orphan Drug Act of 1983 provides benefits and incentives to drug companies that address the more than 7,000 rare diseases that currently exist. To be granted orphan designation, the disease or condition that a drug treats must affect fewer than 200,000 people. If it affects more, the company must prove that it cannot reasonably recoup the costs associated with the drug’s research and development.

Drugs receiving orphan designation are rewarded with seven years of market exclusivity as well as sizable tax credits and other benefits, says Edward Buthusiem

Berkeley Research Group, a strategic advisory and consulting firm.

“Many drugs receiving orphan designation are older versions of drugs which, in several cases, have been on the market for many years and are often without patent protection,” Buthusiem says. “In other words, these drugs are repurposed for use to treat an orphan disease.”

Since the volume of orphan drugs tends to be small, reflecting the limited number of targeted patients, the price of these drugs tends to be much higher than drugs to treat nonorphan drugs, Buthusiem says. The costs of producing and selling these drugs tends to be higher since they are distributed through specialty wholesale channels. However, the price of such drugs also extends to the nonorphan indications of these drugs.

This lack of price differentiation between orphan and nonorphan indications has drawn the ire of Congress, which is seeking to limit the incentives granted to orphan drugs.

The Closing Loopholes for Orphan Drugs Act is one currently pending bill to watch. Currently, orphan drugs are excluded from the 340B program to avoid invalidating company incentives to develop such products. In other words, drug makers are not required under the 340B program to discount orphan drugs. If passed, the pending legislation would limit the 340B drug pricing program's orphan drug exclusion to apply only when a drug is used for the rare condition or disease it was developed to treat.

“That would allow orphan drugs, which are often very expensive, to be discounted under the federal program when they are used for nonorphan diseases or conditions,” Buthusiem says. The discounts would apply to rural, cancer, critical-access, and sole community hospitals.

Also of note when it comes to orphan drugs, in June 2017, the FDA unveiled a strategic plan to eliminate the agency’s existing orphan designation backlog and ensure continued timely responses to all new requests for designation, says John Pappan, MA, MS, program advisor/director of drug regulatory affairs at Long Island University – College of Pharmacy. “This new plan offers orphan drug prescribers a faster pathway to manage their patients’ healthcare and improve their outcomes.”  

Karen Appold is a medical writer in Lehigh Valley, Pennsylvania.

Three Pharmacy Regulations Health Execs Should Watch   

There are roughly 100 autoimmune diseases, plus about 40 more that are immune-based. Total annual direct healthcare costs for these debilitating conditions are nearly double that of cancer treatments, according to the American Autoimmune-Related Diseases Association. For this reason, the stakes in autoimmune disease research are high.

Read on to discover some of the newest innovations affecting common autoimmune diseases.

Much of the focus in lupus research is focused on interferons, which are signaling proteins made and released by cells in response to the presence of pathogens. Interferons have been found to be overproduced in many lupus patients.

"This observation has led to interferon itself being identified as a therapeutic target," says Mary Crow, MD, physician-scientist lupologist, co-chair of the Lupus Research Alliance Scientific Advisory Board, and physician-in-chief of Hospital for Special Surgery. Anifrolumab, in phase 3 clinical trials, is one medication showing promise in this area, she says, noting it's likely that at least one new medication could be approved for use in the next year.

More than 30 clinical trials are ongoing in various phases of lupus drug development, says Rosalind Ramsey-Goldman, MD, DrPH, Solovy Arthritis Research Society Professor of Medicine and medical director of the clinical research unit at Northwestern University in Chicago. In the last six months, several phase 2 trials showed positive results and are likely to move on to the next phase, she adds.

Ustekinumab, which blocks the IL12/23 pathway linked to the pathogenesis of lupus, and previously approved for psoriasis, psoriatic arthritis, and Crohn’s disease, has been evaluated in lupus in a phase 2 trial, Ramsey-Goldman says. One study showed efficacy in the treatment of active lupus and plans are in place for more studies.

Another study is evaluating sirolimus, which is already approved by the FDA for immunosuppression and to prevent rejection after organ transplantation. Ramsey-Goldman says this medication may be useful in lupus to restrict T cell activity.  

Two phase 2 clinical trials in 2016 that are now in phase 3 could result in FDA approval for anifrolumab and voclosporin, a calcineurin inhibitor and immunosuppressant that blocks T cells.

Researchers are also working to identify biomarkers that can help clinicians improve diagnosis and better identify those at risk for developing the disease, Goldman says. Biomarkers may also help clinicians predict flares, as well as how patients will respond to different treatments.

The most effective intervention for celiac disease is to follow a strict gluten-free diet, but this can be difficult, says Peter H.R. Greene, MD, director of the Celiac Disease Center at Columbia University in New York, the Phyllis and Ivan Seidenberg Professor of Medicine at Columbia University Medical Center, and attending physician at New York Presbyterian Hospital.

Though a gluten-free diet is not easy, it is highly effective and safe. This means that all potential therapies and treatments have a high standard to meet to be considered appropriate alternatives. Some research is focusing on altering wheat to remove or detoxify gluten, but there is a general dislike for genetically altered foods, Greene says. There is also research looking at the use of anti-glutenase enzymes that could reduce the damage caused by gluten.

Larazotide, which is entering phase 3 trials, is helpful in reducing symptoms of celiac disease. Budesonide and prednisone, along with other steroids, have been used to reduce symptoms in celiac patients. Researchers are also working on a vaccine that involves the injection of peptides that may protect patients from some gluten contamination, Greene notes, adding that study is moving to phase 2 trials.

More than 20 different immunotherapy targets are also being investigated, one in particular for refractory celiac disease-a particularly bad form of the disease that does not respond to a gluten-free diet "There is a lot of interest, and some of the bigger pharma companies are getting involved," Greene says.

Kathy Costello, adult nurse practitioner and associate vice president of clinical care for the National Multiple Sclerosis Society, says several genes have been identified as posing a risk for multiple sclerosis development, but there’s not enough definitive data yet to prevent the disease onset through gene therapy.

There are many new developments in treatment on the horizon, though, including an oral medication that was approved for relapsing forms of multiple sclerosis. Fingolimod, approved for adult MS patients since 2010, received a breakthrough therapy designation from the FDA for children and adolescents ages 10 years and older with relapsing MS.

Other medications are in development that restrict the activation and circulation of immune cells, therefore reducing the inflammatory process in multiple sclerosis.

Another medication to watch is ibudilast, used in Japan and Korea for a variety of issues like post-stroke and bronchial asthma since the 1980s. Researchers are looking into the medication's potential benefit for problems including multiple sclerosis, amyotrophic lateral sclerosis, substance abuse, and neuropathic pain, Costello says. In recent phase 2 clinical studies, patients experienced a significant reduction in the progression of whole brain atrophy. The research may move to phase 3 trials soon and ibudilast has been designated as a fast-track product in terms of its development as a possible treatment for progressive MS, says Costello.

Additional treatments in the research pipeline have a similar focus, by reducing activation of the immune system, reducing the activation of immune cells, or blocking the entry of those cells into the central nervous system.

"They're each coming at the immune system problems from various directions. This is good news for people with multiple sclerosis who may need to switch to a different medication due to a suboptimal response or side effects. Having medications with differing mechanisms of action will allow greater chance to impact the disease process,” says Costello.  

There is also interest in how gut microbiota and exercise can impact multiple sclerosis, particularly regarding what exercises are best for stimulating different parts of the brain and improving mobility.

Stem cells transplants may also be an option. "Interim results from a study of hematopoietic stem cell transplant showed the procedure was well-tolerated and there may be benefit to rebooting the immune system," Costello says. "You are essentially suppressing the immune system and then reintroducing the patient's own stem cells, and in multiple sclerosis the hope is they will regenerate in a less harmful way.  

Jessica L. Dunne, PhD, research director at the Juvenile Diabetes Research Foundation, says development of treatments for type 1 diabetes has been slow, partly because insulin works so well in treating it.

"While insulin may seem on the surface like a great therapy, and it is, there's still a burden of maintaining adequate blood sugars," Dunne says.

Technology may help, with insulin pumps, implantable monitors, and other devices easing the burden of the disease for some patients. Continuous glucose monitors are becoming more readily available, with a 20% uptake in use over recent years, and studies show they lead to improved outcomes, Dunne says.

There is also some progress in medication development, with researchers looking into new immunotherapies like SGLT 1 and 2 inhibitors. These inhibitors affect glucose absorption in the kidneys, providing glycemic control in a new way outside of simply increasing insulin levels. Researchers are also looking into encapsulating and implanting beta or islet cells into patients that could potentially reduce or eliminate the need for insulin therapy for the life of those implanted cells.

Increased interest in adjunct therapies like this for type 1 diabetes will improve access for patients, Dunne says. "It will make them easier to prescribe and improve insurance coverage," she says. "It's a huge step. I hope this opens the door for more adjunct therapies."

There are also studies investigating the role of cytokine inhibitors and antigen-specific therapies, a viral vaccine that may prevent the development of type 1 diabetes, and how the gut microbiome affects disease development and progress, she says.

"There has been some evidence showing the microbiome is changed in diabetes, but the big question now is, what do we do about it?" Dunne says.

Christopher Morris, MD, a Tennessee board-certified rheumatologist who serves on the government affairs committee for the American College of Rheumatology and on the board of directors for the Southern Medical Association, says biologics, such as adalimumab (the top-selling medication in the world) have shown tremendous progress in treating RA. Still, the cost of these new treatments can be prohibitive, Morris says, and the problem is compounded in rheumatology because there are so few FDA-approved medications and treatments are often used off-label. Patients have trouble getting medications approved for coverage by insurance companies, and can rarely afford them on their own, he says.

“This is something we are frustrated with in medicine. My first consideration when I write a patient a medication is, are they able to afford it?" Morris says. "We want a medicine that works and we want a medicine they can afford."

Biosimilars could be a more cost-effective alternative to biologics, he says, but there is hesitation over fears that cost savings could come at the expense of efficacy.

He says Janus kinase (JAK) inhibitors are likely the next big thing in treating RA, and future treatments are becoming increasingly selective to improve efficacy while reducing negative effects.

There has also been some research into vagal nerve stimulation-which usually involves either manual or electrical stimulation of the vagal nerve, Morris says, highlighting the idea that there is a neurologic component to some autoimmune diseases. "Maybe by modifying how the body is reacting neurologically, it can have an effect on rheumatoid arthritis.”

New medications being investigated for psoriasis and psoriatic arthritis include JAK inhibitors. Upadacitinib, for example, is being studied for use in psoriasis, psoriatic arthritis, atopic dermatitis, and other autoimmune diseases like Crohn's, says Morris. The once-a-day medication is now in phase 3 trials, he says. "It's an interesting medicine. We want to see what pro-inflammation markers are there and direct against that."

The issue with the psoriasis family of diseases and other autoimmune conditions, he says, is finding balance between toning down the immune system response to pathogens that trigger the conditions, without damaging the immune system too much.   "Every one of these medicines is playing with your immune system."

Rheumatologists need to look at a patient's individual symptoms and condition to determine the best medications for them. For example, ustekinumab works well for psoriasis, but is not the first choice for patients with joint problems. Adalimumab, on the other hand, is approved for both, says Morris. “The more different approaches we have, the better.”

Top Autoimmune Disease Treatment Developments to Watch 

Unique trends are occurring in the pharmaceutical pipeline that would have been unheard of just five years ago. One agent coming on the market may cost up to $1 million for a one-time infusion, and a new agent derived from cannabis may be the first of many such products for a host of illnesses.

 editorial advisor, and CEO of the Pharmacy Group consulting firm, says some remarkable agents will be coming on the market that will significantly help individuals who previously had no treatment options.

Here, industry experts share more information about noteworthy new drugs in the pipeline.

: AveXis, Inc., which is a clinical-stage gene therapy company, says it is using an adenoâassociated virus vector (AAV9) containing the SMN1 transgene for the treatment of spinal muscular atrophy (SMA) infusion (one-time). The company says about 7,200 infants have SMA Type 1, which represents infants from birth to six months of age. Babies with SMA Type 1 have difficulty breathing and swallowing. They cannot sit, crawl or walk and only 8% of babies with SMA Type 1 survive to 20 months of age. 

: All patients in the therapeutic dose cohort in the phase 1 trial were alive and event-free at 24-month follow-up. Patients observed in long-term follow-up from the phase 1 trial continued to gain strength and achieve new milestones, including two additional patients who could stand with assistance.

: Orphan drug. Biologics License Application (BLA) filing possible in mid-2018 with approval in late-2018 or early-2019, according to Christopher Peterson, PharmD, director, clinical evaluation and policy, Express Scripts.

Cost estimate: $750,000 to $1 million for the one-time infusion, according to Peterson.

AVXS-101 could be the first one-time gene replacement therapy for SMA, a disease which results in early death or lifelong disability with considerable healthcare costs. It is expected to be available in the U.S. in 2019.

Sukumar Nagendran, is chief medical officer and senior vice president of AveXis, which is developing this product. He expects to submit a request for a pre-BLA meeting with FDA by the end of June to discuss the regulatory path for AVXS-101. “We will be able to provide more guidance after the meeting minutes are received, typically approximately a month after the meeting,” says Nagendran

: Purified cannabidiol (CBD) without any psychoactive properties for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), rare forms of epilepsy. It is an oral liquid therapy (once daily). GW Pharmaceuticals says about 18,000 patients in U.S. have LGS and 8,000 have Dravet syndrome. Lennox-Gastaut syndrome typically occurs between the ages of 3 to 5 years. Dravet syndrome affects infants. Both conditions can cause severe intellectual and developmental disabilities and early death.

: In clinical trials, cannabidiol was effective in lowering seizure rates in these patients.

: Orphan drug with approval expected by June 27, 2018, according to Aimee Tharaldson, PharmD, senior clinical pharmacist advisor, Express Scripts.

: More than $100,000 per year, according to Tharaldson.

Cannabidiol is a pharmaceutical formulation of purified cannabidiol. GW Pharmaceuticals reported in phase 3 studies that cannabidiol added to other antiepileptic therapies significantly reduced the frequency of seizures in patients with LGS and Dravet syndrome. If approved, this agent would be the first pharmaceutical formulation of purified, plant-based CBD, according to GW Pharmaceuticals This product is a cannabinoid lacking the high associated with marijuana and it would be the first in a new category of anti-epileptic drugs, according to GW Pharmaceuticals. Aimee Tharaldson, PharmD, senior clinical pharmacist advisor, Express Scripts says cannabidiol looks like a promising drug that could be a gamechanger for these patients. “There is a need for new treatment options for these patients. In three pivotal clinical studies, Epidiolex demonstrated strong efficacy in reducing seizure frequency in patients with LGS and DS,” Tharaldson says. 

: Larotrectinib (LOXO-101) is a potent, oral and selective investigational new drug for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs), according to Lovo Oncology, which is developing this agent.

: A drug targeting a gene fusion that occurs in lung, colon, and other cancers, larotrectinib was shown to be effective in 75% of patients of all ages in clinical trials, and an even higher percentage of pediatric patients, according to study investigators at UT Southwestern’s Simmons Cancer Center.

: The drug has been granted FDA fast-track consideration. It is under FDA review and a decision is expected by December 2018, according to Ted Laetsch, MD, assistant professor of pediatrics and with the Harold C. Simmons Comprehensive Cancer Center.

Most cancer drugs are targeted to specific organs or locations in the body. Larotrectinib is the first cancer drug to receive FDA breakthrough therapy designation for patients with a specific fusion of two genes in the cancer cell, no matter what cancer type, according to Laetsch. While the TRK fusions occur in only a small percentage of common adult cancers, they occur frequently in some rare pediatric cancers, such as infantile fibrosarcoma, cellular congenital mesoblastic nephroma, and papillary thyroid cancer, says Laetsch. 

“I do think this is a gamechanger,” Laetsch says. “Larotrectinib has received breakthrough designation for the treatment of patients with a TRK fusion positive solid tumor, regardless of the type of tumor in which that fusion occurs. I see this as the next big step in the development of precision medicine and molecularly targeted therapy.”

: A calcitonin gene-related peptide (CGRP) receptor antagonist monoclonal antibody for prevention of migraine in patients with four or more migraine days per month. It is given by subcutaneous injection monthly, according to Peterson.

: Research published in November 2017 in The New England Journal of Medicine reported positive results from the six-month phase 3 STRIVE study evaluating the drug versus a placebo for the prevention of episodic migraine. It found that the drug delivered clinically meaningful and statistically significant differences from placebo for all primary and secondary endpoints in a study that included 955 patients. Patients taking this agent experienced a significant reduction in mean monthly migraine days and were significantly more likely to achieve a 50% or greater reduction in monthly migraine days than those taking placebo.

: Under FDA review at press time with a PDFUA date of May 17, 2018 (deadline by which the FDA must review new drug applications), according to Peterson.

: Approximately $9,000 per year, according to Tharaldson.

“The new CGRP inhibitor class of medications will provide a treatment option for patients with chronic or episodic migraines,” says Christopher Peterson, PharmD, director, clinical evaluation and policy, Express Scripts. “Many of these patients are resistant or intolerant to currently available therapies. As a debilitating condition, decreasing the number of migraine days in patients with chronic or episodic migraines is an important advancement for these patients.”

: A dual SGLT1 and SGLT2 inhibitor for use in combination with insulin therapy to improve glycemic control in adults with type 1 diabetes mellitus, according to Peterson. He says the dual inhibitor of SGLT-1 and SGLT-2 can influence how the intestines and kidneys process blood sugar, respectively. It is also under investigation for treating type 2 diabetes. It is a once-daily oral therapy, according to Peterson.

Unique trends are occurring in the pharmaceutical pipeline that would have been unheard of just five years ago.

Vol 28 No 6