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As the number of rare disease drugs on the market exponentially increases, marketers will have to ramp up efforts to persuade payers of the value of these often costly treatments.

By Christiane Truelove | email hidden; JavaScript is required

The pipeline of drugs to treat rare diseases continues to grow, as well as the number of drugs approved for these diseases. According to the FDA’s Center for Drug Evaluation and Research (CDER), in 2022, more than half (20 of 37, or 54 percent) of novel drug approvals were for patients with rare diseases. These approvals include Xenpozyme (olipudase alfa) in pediatric and adult patients with acid sphingomyelinase deficiency (ASMD), a rare genetic disease that causes premature death; Dupixent (dupilumab) injection for the treatment of adults with prurigo nodularis (PN); and Camzyos (mavacamten) capsules to treat adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (oHCM) to improve functional capacity and symptoms.

Regulators are trying to widen the rare disease pipeline. In May 2022, CDER launched the Accelerating Rare disease Cures (ARC) Program, which is set up to harness the agency’s collective expertise and activities to drive scientific and regulatory innovation for rare diseases, and builds upon CDER’s existing capabilities to expand its interactions with the rare disease stakeholder community. The program’s goal is speeding and increasing the development of effective and safe treatment options to address the unmet needs of patients with rare diseases.

CDER officials say the program has multiple efforts under way to support rare disease drug development, such as Learning and Education to Advance and Empower Rare Disease Drug Developers (LEADER 3D) to better understand the challenges in bringing rare disease drug products to market. As part of LEADER 3D, CDER is seeking input to help identify knowledge gaps and produce educational materials on fundamental topics important to stakeholders, such as nonclinical and clinical pharmacology considerations; clinical trial design and interpretation; and regulatory considerations for rare disease drug development.

According to Vision Research Reports, the rare diseases treatment market surpassed $119 billion in 2021 and is expected to hit around $336 billion by 2030, growing at a CAGR of 12.15 percent from 2022 to 2030. Treatments for cancer dominated the market in 2021 with a revenue share of more than 25 percent, and the injectable segment dominated the market with a revenue share of more than 50 percent and is expected to witness significant growth during the forecast period. Biologics had a revenue share of more than 55 percent in 2021.

The Global Genes Project estimates that 300 million people globally suffer from uncommon diseases. As testing and diagnosis improve and more patients are determined to have a rare disease, the use of rare disease therapies will increase.

About 6-8 percent of people in the European Union are thought to be affected by a rare disorder, according to estimates from the European Organization for Rare Diseases (EURORDIS).

Under the influence of the U.S. Orphan Drug Act, which grants financial incentives to pharma companies developing rare disease drugs, the number of drugs has grown – but so have the prices. According to a report by the Institute for Clinical and Economic Review, “The Next Generation of Rare Disease Drug Policy: Ensuring Both Innovation and Affordability,” the rapid growth in approved rare disease treatments has created concerns about the pricing of these drugs and their cumulative affordability to the health system. ICER experts state that in 2019, the average annual cost of an orphan treatment per treated patient was $32,000, with treatments ranging from $6,000 to $500,000 per year. However, data from internal payers suggest a growing number of patients with treatments costing $1 million or more per year, with 39 percent of orphan drugs costing more than $100,000 annually, and gene and cell therapies (see related article on p. 21) costing hundreds of thousands of dollars or more. If a drug is priced at $100,000 per year and has a treated patient population of only 10,000 individuals, it produces revenues of $1 billion per year.

ICER experts say some people no longer see the primary challenge related to orphan drugs as that of creating a viable business model, but in “absorbing the cost of a growing wave of high-priced orphan drugs that may threaten sustainable insurance premium levels and throw up greater barriers to access for individual patients.” These experts maintain that some health plans have restricted access to these treatments.

“As of 2018, an analysis of private health plan coverage decisions for specialty products found that plans excluded coverage for orphan products only 1 percent of the time, but coverage for all orphan drugs was restricted in 29 percent of coverage policies, ranging from 11 percent to 65 percent across plans,” ICER experts say. “However, coverage for orphan products was less restrictive than for non-orphan specialty drugs, which faced coverage restrictions 4 percent of the time and exclusions 6 percent of the time. From diagnosis to treatment availability, to plan coverage, people with rare diseases face many challenges to gaining effective, timely, and affordable treatment for their condition.”

According to ICER, spending for orphan indications increased from two percent of invoice spending on drugs in 1992 to 11 percent in 2019. “Payers have limited tools with which to manage the high costs for orphan drugs,” these experts say. “However, payers usually do apply utilization management restrictions on orphan products in an effort to encourage evidence-based prescribing and manage costs” such as prior authorization. For example, in 2016, 76 percent of orphan drugs in Medicare Part D were subject to prior authorization. And as the portion of employers who self-fund their insurance continues to rise, many have adopted “stop loss” or reinsurance policies as one mechanism to help manage extremely high, unanticipated costs that can be associated with some orphan treatments, particularly cell and gene therapies.

“However, not all employers can afford benefit designs including stop loss insurance,” ICER says. “In addition, a recent report suggests that the current contracts between self-insured companies and stop loss carriers may no longer be cost-effective in mitigating the financial risk associated with gene and cell therapies, particularly as a wave of new gene and cell therapies enter the market in the coming years.”

ICER experts found that some plan sponsors are stripping out cell and gene therapies entirely from their health benefits. The health plan and PBM executives they interviewed have indicated that they experience regular and growing pressure from self-insured employers to exclude coverage for these products, and “anticipate that this trend will only increase.”

Facilitating access from the pharma side

Christopher Ngai, Calliditas
Christopher Ngai, VP, market access, at Calliditas Therapeutics

For companies developing rare disease treatments, even if these are not cell or gene therapies, there is still an intensive amount of work marketers need to do to persuade payers to cover these treatments. According to Christopher Ngai, VP, market access, at Calliditas Therapeutics, although payers’ evidentiary requirements continue to rise, what they have been asking for has been “pretty consistent. A key learning for me has been that when you are the first groundbreaker or innovator, or pioneer in a disease, or bring the first treatment to space where there has not been any innovation for a long time, oftentimes there’s a requirement to educate the providers, to set that expectation – that is very critical,” he says.

Calliditas’ product, Tarpeyo, was approved by FDA via accelerated approval in December 2021 and launched in January 2022. The drug is used to reduce levels of protein in the urine (proteinuria) in adults with a kidney disease called primary immunoglobulin A nephropathy (IgAN) who are at high risk of disease progression.

Ngai says launches for drugs such as Tarpeyo, aimed at particular patient groups with needs that payers are not used to dealing with, offers challenges around making sure these patients are getting the access that they deserve. “The other part is that patients need to be educated on how to advocate for their own health.”

In one sense, rare disease patients are already longtime advocates for treatment innovation, Ngai says, and marketers should help them. “Once an innovation does arrive on the marketplace, there should be equal focus and vigor in terms of championing for access, that’s working with the providers, with the manufacturers, and with the insurers,” he says, adding that once all of these elements are in place, a treatment launch into the rare disease space can be successful.

Tarpeyo
Tarpeyo was launched by Calliditas Therapeutics in 2022 to reduce levels of protein in the urine in adults with primary immunoglobulin A nephropathy (IgAN).

For Tarpeyo, Calliditas has built an access program that provides “care navigators” for providers and patients. These care navigators provide a point of contact between physicians and patients and the payers. “Once we receive an enrollment form, along with a prescription form from the physician side, we reach out to them to obtain the necessary medical records, lab results, etc., that we know our payers are asking for, to demonstrate a medical need,” Ngai says.

The care navigators help get about 80 percent of those prescribed Tarpeyo successfully on the therapy and receiving treatment.

In the year since the product launched, with the access program, Calliditas has seen patients able to get on Tarpeyo less than 30 days after being prescribed the drug. But Ngai says the “right question” to ask now is how access can be improved to get patients on Tarpeyo even more quickly.

The company has a goal that when a physician writes a prescription for Tarpeyo, within three days the drug is actually in the hands of the patients. Along with receiving the drug, patients get a consultation with a pharmacist to talk them through what they should expect, which creates “a dialogue platform” for them to reach out if they have any questions. “We do have a nurse staff on the program to actually address those kind of questions,” Ngai adds.

When it comes to persuading payers to put Tarpeyo on their formularies and improve access, Calliditas has found that an economic argument works.

“This is a repeated pattern that always happens when you have an innovative product that has been proven to be effective in addressing a disease, especially a disease like kidney disease, where the long-term cost is very high,” Ngai says.

The most common way to address chronic kidney failure due to IgA nephropathy is dialysis, “which can last for many years and at a very high cost to society and patients,” Ngai says. “The other [option] is a transplant, where most patients after transplant need to be on lifelong immunosuppressants to keep the organs working.”

In Calliditas’ case, the company was the first to get a treatment approved for reducing protein levels in the urine for IgA nephropathy. “We also have the only sort of treatment in this disease being studied, and now of course approved, targeting a very unique aspect of the disease cascade,” Ngai says. “So given that uniqueness and the value that ultimately we deliver to the patients – and we actually have shown that in a cost effectiveness analysis – we believe this is a cost-effective treatment.

“So from that perspective, this is how we’re interacting with our payers to help them understand the value to the patients, and some of the immediate value that I can see, for example, is potentially delaying the transition from one CKD [chronic kidney disease] stage to another one.”

Because Tarpeyo was approved under the accelerated approval process, Calliditas continues to study the drug and build more evidence for regulators to verify the clinical benefit of slowing kidney function decline. In March, Calliditas had a positive readout from its NeflgArd Phase III study for Nefecon.

The trial met its primary endpoint with Nefecon demonstrating a highly statistically significant benefit over placebo (p value < 0.0001) in estimated glomerular filtration rate (eGFR) over the two-year period of nine months of treatment with Nefecon or placebo and 15 months of follow-up off drug. Additionally, supportive two-year total slope analyses were statistically significant and clinically meaningful, reflecting a sustained treatment benefit.

The next step for Calliditas will be asking FDA for full approval, and when that happens, the company will approach the payers again, Ngai says, using the confirmatory data to address some of their previous concerns, and then working with them to remove some of the add-on barriers that were put in place for a broader, on-label population reimbursement.

Cem Zorular, Er-Kim
Cem Zorlular, CEO, Er-Kim Pharmaceuticals

Cem Zorlular is CEO 0f Er-Kim Pharmaceuticals in Turkey, a company that works with small to large pharma and biotech companies to commercialize their medicines in markets that fall outside the United States and the Western Europe. “We work the whole gamut of getting the products registered, reimbursed, and delivering access to the patients,” Zorlular says.

The markets Er-Kim works in – the Central Eastern and Eastern Europe regions, as well as Middle East, North Africa, and Turkey – follow the examples of Western European and U.S. payers. “So as a result of that, we have to develop a key understanding on how these payers are thinking, how they’re approaching, and how they’re planning to change the way they look at things,” Zorlular says. “So therefore, we basically as a company need to develop a very keen understanding of the way the west thinks – and by that I mean the Western markets, the U.S. and Western Europe – to better anticipate how our regulators are going to approach an issue, and also how our market sits in terms of other pharmaceutical markets. As price goes up, it becomes less expensive in our markets, whereupon relative price might go up in the future if the Western regulators change their approach to pricing as well.”

At present, when it comes to funding and accessing treatments for rare diseases, “we’re actually in a position where our regions are coming from relative lower funding to higher funding – there is increased support from the European Union, and there is increased economic development in the countries [in which] we work,” he says. “So overall, we’re actually seeing an increasingly positive environment for the patients to be able to access to rare disease medicines, in terms of reimbursement and price negotiations.”

When payers determine if the new technology offered by a rare disease medicine justifies the cost, Er-Kim works with them to build an access plan that ensures that there is enough budget, and the budget is being used properly for these patients, Zorlular told Med Ad News.

There is also an increasing focus among these payers to think more holistically about rare diseases. “A number of regulators are not only funding the rare disease treatments, but they’re also working with us or our partners or other companies like us to improve the diagnosis of rare diseases … prevention methodology such as genetic screening prior to marriage, counseling couples to make sure that if they have a higher chance of having a baby with a congenital disease, they are warned ahead of time,” Zorlular says.

Although the Eastern European payers follow EMA single market rules, other regions that Er-Kim is active in do not, and therefore are a bit more flexible when it comes to access negotiations for rare disease drugs. “But the additional flexibility comes by looking at the U.S., and they don’t look at U.S. payers, but U.S. practices,” Zorlular says. “When you’re in a negotiation discussion, [if] the product is in the guidelines in the U.S., what FDA says does come into discussion a bit more. But from a reimbursement perspective, Europe has a very high reputation of negotiating very strongly. So therefore, once there’s a price in Europe, then that becomes the main center of discussion.”

And when it comes to patient access programs for rare diseases, these regions are investing more, Zorlular says. “Overall, budgets are increasing. And there is increasing willingness to build unique programs to improve access. But one thing that’s nice to further develop is the infrastructure. You can talk about very advanced payment methods and look at results-based payments, but they need to come with a very strong infrastructure to track those outcomes. And that’s why these are not necessarily being favorites above more traditional access pathways. That doesn’t that there is lack of innovation, but usually innovation comes from the perspective of having simple but innovative access models.”

And by infrastructure, Zorlular is referring ways of tracking, storing, and processing healthcare data. “Certain payment models are specifically built around being able to properly collect data, validate the data, and analyze it in a way that makes all sides comfortable with the results. And that requires a fair bit of IT infrastructure favor of connection in terms of national databases, and this is not as uniformly available as it is in other countries,” he says.

At the end of the day, “these are growing countries, and some have very high budgets,” Zorlular says. “But overall, budget allocation might be an important consideration.”

Rare disease access programs have been benefiting in these regions as part of a general push to continuously invest in overall health, because it’s an important driver of the country’s growth, Zorlular says. For example, in Eastern Europe, programs are being started to battle antimicrobial resistance, cancer, and heart disease.

And in rare diseases, one country established a national registry of a rare disease and is trying to implement birth screening. “Turkey is actually one country that is very forward thinking when it comes to these types of measures, investing in decreasing the incidence of congenital diseases through population counseling,” Zorlular says. “Overall, we’re seeing that being changed into an investment mindset, if not maybe more than what we’re seeing in Western Europe.”

Chris Truelove, Med Ad News Chris Truelove is contributing editor of Med Ad News and PharmaLive.com.