Orphan Drug Development in Cardiovascular Medicine

Developing novel therapies that are safe and effective is challenging, but achieving acceptable certainty of both is imperative. Rigorous evaluation of the safety and efficacy of investigational therapeutics in the estimated 6000 orphan disease settings is especially difficult. While orphan drug approvals have been mostly for oncological indications, the recent approval by the US Food and Drug Administration (FDA) of tafamidis for transthyretin amyloid cardiomyopathy allows for critical appraisal of necessary science supporting this pathway. Assessing such considerations are especially worthwhile considering the increasing sophistication of cardiovascular characterization that will likely result in many niche phenotypes within any given disease state.

Why Is Orphan Drug Development so Challenging?

Target populations are inherently small, geographically dispersed, and may be challenging to identify due to variable availability of necessary diagnostic testing. Smaller studies with limited number of events are at risk for chance findings and false positive results. Many novel heart failure therapies have shown disconnect between smaller phase II trials versus the adequately powered larger phase III studies (Table). Early phase evaluation of therapies that were promising invariably had fewer than 100 to 150 events, but when larger trials with over 500 events accrued were conducted, these earlier results could not be replicated in the best or reversed in the worst-case scenario. Caution should be practiced when interpreting trials with relatively small sample sizes and low event rates, especially when only a single trial has been conducted.

FDA Approval of Tafamidis

In May 2019, tafamidis was approved by the FDA for the treatment of transthyretin cardiac amyloidosis. Tafamidis was approved as an orphan drug—a designation reserved for drug treating a disease that affects <200 000 people in the United States. The expedited approval was based on the ATTR-ACT trial (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial), which randomized 441 patients with transthyretin amyloid cardiomyopathy to tafamidis or placebo for 30 months.¹ The investigators hierarchically assessed all-cause mortality followed by cardiovascular hospitalizations using the Finkelstein-Schoenfeld method. Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] versus 76 of 177 [42.9%]; hazard ratio, 0.70 [95% CI, 0.51–0.96]) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 versus 0.70 per year [95% CI, 0.56–0.81]). The number needed to treat for all-cause mortality and cardiovascular-related hospitalizations was 7.5 and 4, respectively. Tafamidis also significantly improved other patient-centered outcomes, such as health-related quality of life and functional capacity.¹

Is Tafamidis Worth the Price?

Tafamidis has been priced at $225 000 a year, making it the most expensive cardiovascular drug. A cost-effectiveness analysis based on ATTR-ACT has estimated $880 000 per quality-adjusted life-years gained, which would require a 93% price reduction to $16 563 to be considered cost-effective at conventional thresholds.² While cancer therapies have more commonly used orphan drug approval pathways, it is important to note that tafamidis may be expected to be used for lifetime compared with cancer therapies that are taken for a more limited duration, resulting in crucial cost implications.

As the current FDA label supports its use to “reduce cardiovascular mortality and cardiovascular-related hospitalization,” enthusiasm surrounding the absolute risk reduction should be tempered based on lack of real-world evidence and lack of a second supportive trial. In addition to potential regulatory implications, ascertaining and quantifying benefits on key end points is important in valuation of a therapy. The potential for mortality reduction (and its certainty) that was considered when establishing initial listing price of tafamidis may be discussed in the context of shared decision-making with patients and caregivers. Moreover, with better screening and improved awareness of transthyretin amyloid cardiomyopathy, the number of patients with this diagnosis can exponentially increase. Furthermore, due to the high cost of tafamidis, it will be hard to assess alternative treatment options in comparison to tafamidis. Thus, the extremely high cost of tafamidis raises important concerns about affordability and sustainable access to therapies for patients with diseases that might not be that rare. Though tafamidis is beneficial for patients, the high prices are not justified.

Approval Process of Orphan Drugs

Another example of an approved cardiovascular orphan drug is the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, evolocumab, for the treatment of homozygous familial hypercholesterolemia. The FDA approved evolocumab for homozygous familial hypercholesterolemia based on the TESLA trial (Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormality), which enrolled 49 patients.³ Evolocumab significantly reduced LDL (low-density lipoprotein) cholesterol at 12 weeks by 31% compared with placebo. No serious clinical adverse events were observed. Evolocumab was initially priced at >$14 000 per patient per year, which was later reduced by 60% owing to payer push back.

Although conducting trials with orphan drugs has unique challenges of small patient population sizes and difficulties in finding feasible study sites,⁴ the need for only 1 trial and the development of established pathways of approval suggest that orphan drug development may be easier with equal or even greater financial rewards. Since the Orphan Drug Act in 1983, which provided financial incentives for development of new drugs for rare diseases, >500 products for rare diseases have received approval. In the last 5 years 1 of 3 all new drug approvals was for rare diseases. It is important to note that the requirement of “substantial evidence that the drug will have its claimed effect” for drug approval is the same for all drugs whether they are for common or rare diseases.

It is understandable that conducting large adequately powered trials for orphan drugs may be impossible. To enhance the statistical rigor of smaller studies, win ratio method has been proposed. Instead of the traditional time-to-event analysis using a composite end point, win ratio method does not ignore the repeat hospitalizations or death, which happen after the first index event. This results in greater power and might be an attractive option for small sample trials such as those of orphan drugs. Furthermore, while the European Medicines Agency applies a restricted definition of orphan diseases limited to conditions that affect <10 000 people, in the United States, the FDA defines orphan diseases as those that affect <200 000 people. As such, not all orphan diseases are truly rare, and many can be tested in the same trials (and with the same rigorous standards) typically used in cardiovascular research.

Conclusions

Orphan drug development pathways are currently protected by a lower evidentiary bar, special marketing incentives, and have traditionally been priced much higher. Transparent cost-effectiveness analysis should be done for all cardiovascular orphan drugs and pricing should be accordingly evaluated. Furthermore, true population prevalence for certain rare cardiovascular conditions may in fact be much larger than allowed by orphan disease designations. Suboptimal application of orphan disease status to not uncommon, but underdiagnosed, conditions has the potential to result in pricing structures that may significantly limit access to lifesaving therapies and create multiple unaffordable drugs. We suggest that as disease awareness and screening increases may dynamically change the eligible population; hence, pricing of orphan drugs should be regularly reevaluated.

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