What, Me Worry?

The U.S. Food and Drug Administration’s Center for Drug Evaluation and Research set a record in 2018 by approving 86 orphan drugs, surpassing the previous record of 77 orphan drugs the agency approved in 2017.

What’s more, of the orphan drugs approved in 2018, 34 represented new molecular entities. In fact, orphan drug approvals represented slightly more than half of the 59 new molecular entities approved by the agency in 2018, besting the record set in 1996 when the FDA approved 53 new molecular entities. About a third of the orphan new molecular entities approved in 2018 were for cancer indications.

With about 7,000 rare diseases identified and with approved therapies to treat only about 5 percent of those conditions, the addition of new drugs to the arsenal is good news. While the latest slate of approvals is encouraging, the reality remains that most rare diseases are without therapeutic options today. And while the rare disease pipeline is full of promise, sustainability is a concern.

Though it’s difficult to draw conclusions about long-term trends from a single year, the increased number of approvals is positive, and the pipeline suggests the pace will continue. There are more than 560 medicines that are in clinical development to treat orphan diseases, according to an October 2018 report from the trade group the Pharmaceutical Research and Manufacturers of America.

There were several noteworthy approvals in 2018. They included Epidolex, a treatment for two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients two years of age and older. Epidolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana.

Onpattro, an infusion for the treatment of adults with peripheral nerve disease caused by hereditary transthyretin-mediated amyloidosis (hATTR), also won approval in 2018. hATTR is a rare, debilitating, and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart, and other organs. Onpattro is not only the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, but it is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment.

Also noteworthy is the FDA approval of Crysvita, the first drug approved to treat adults and children ages 1 year and older with x-linked hypophosphatemia (XLH), a rare, inherited form of rickets. XLH is a serious disease affecting approximately 3,000 children and 12,000 adults in the United States. Most children with XLH experience bowed or bent legs, short stature, bone pain and severe dental pain. Some adults with XLH experience persistent discomfort or complications, such as joint pain, impaired mobility, tooth abscesses, and hearing loss.

A complete list of the FDA Orphan Drug approvals in 2018 can be found on the RAREDaily website here.

Perhaps the biggest threat to continued innovation is not scientific or regulatory, but economic. As EvaluatePharma noted in its Orphan Drug Report 2018, some of the newer orphan drugs faced hurdles with payers. As new therapies move toward market with the potential for record-setting price tags, it is payers, not regulators, who appear to have the final word on whether patients will be able to access new therapies.

The report noted a recent survey by the Pharmacy Benefit Management Institute that showed cost is the primary concern for 55 percent of payers, and 71 percent do not believe that current prices are sustainable. “As such,” wrote Evaluate, “it will be difficult to predict the market impact of these types of innovation that will test existing payment models to their limits.”

Evaluate noted that pricing pressure is not the only threat to advancing innovative therapies in the rare disease sector. It cited the U.S. tax reform legislation slashed the tax credit for orphan drug developers from 50 percent to 25 percent. “As such, the orphan drug market is at an interesting crossroads in its development,” Evaluate continued. “On the one hand with the cost of development set to rise and increasing payer push-back, the sector could become less attractive for both smaller and larger companies.”

With contenders from the 2020 presidential race in the United States starting to step forward, ongoing legal challenges to the Affordable Care Act, and efforts by the Trump administration to dismantle the ACA, there are clear signs that healthcare will move to center stage in election year debates. Drug prices will likely be ensnared in the political theater that is ahead.

We are at a time when a long-term investment in innovation is starting to pay off in groundbreaking therapies with the promise of saving lives and radically improving the quality of lives of patients with disabling conditions. There’s been a tendency in the rare disease community to believe the unique circumstances of these conditions—the small patient numbers and the often-dramatic impact of therapies—would insulate rare disease therapies from feeling the squeeze from payers. But some large pharmaceutical companies have stepped away from rare diseases and payers outside the United States have been willing to say some therapies are too expensive, even though they may be the only option for a rare and deadly disease.

It is essential that rare disease advocates think broadly about innovation and that innovation be extended into all areas of drug discovery, development, delivery, and manufacturing. New ways will be needed to reduce the time, cost, and risk of developing drugs in order to maintain the sustainability of rare disease therapies if drugmakers are going to continue to drive products to market and investors are going to continue to back them. Wishful thinking may not be the best strategy.

January 2, 2019

 This story was updated January 15, 2019 to correct the number of orphan NMEs approved in 2018.