Niemann-Pick disease: FDA approves first two drugs in the space of a week for rare disorder

The U.S. Food and Drug Administration (FDA) recently approved the first two drugs to treat the rare lysosomal storage disorder Niemann-Pick disease type C. Both of these drugs were given the green light within the space of a week, finally offering patients the first-ever treatments for the disease, which is ultimately fatal, as individuals affected only live for around 13 years on average. 

On September 20, Zevra Therapeutics received FDA approval for its drug arimoclomol, sold under the brand name Miplyffa, to be used in combination with Johnson & Johnson (J&J)’s Zavesca. This was seen as a huge win for Zevra. However, just a few days later, on September 25, an approval for IntraBio’s monotherapy levacetylleucine (Aqneursa) dealt a potential blow to its success. 

In this article, we take a closer look at the details of these approvals, as well as explain exactly what Niemann-Pick disease type C is and how it affects patients. 

What is Niemann-Pick disease type C?

Niemann-Pick disease is a rare genetic disease that results in progressive neurological symptoms and organ dysfunction. Patients with the disease have a mutation in either the NPC1 or NPC2 gene, which affects the necessary transport of cholesterol and other lipids within a cell. As a result, these cells do not function as they should, ultimately leading to neurological symptoms including speech and cognitive difficulties, and organ damage. 

Signs and symptoms of the disease generally first appear in childhood, but they can present at any time, including adolescence or adulthood. Signs and symptoms become more pronounced over time due to the progressive nature of the disease.

Prior to the two recent approvals, there were no treatments for Niemann-Pick disease, with the only option being to manage it as best as possible with pain medications, physical therapy, and speech therapy. 

Miplyffa: The first-ever FDA-approved treatment for Niemann-Pick disease

It hasn’t always been plain sailing for Zevra’s arimoclomol. It once belonged to Danish biotech Orphazyme, which was known as a “meme stock” company, whose price was influenced by social media. The company initially saw high valuations, but in 2021, the FDA rejected arimoclomol, requesting more data on the drug. Ultimately, this led to Zevra – known as KemPharm at the time – acquiring Orphazyme and its drug in 2022 in a $12.8 million deal. 

The original approval bid for Miplyffa hinged on data from a study that utilized a measure of disease severity known as the 5-domain Niemann-Pick disease Clinical Severity Scale (5DNPCCSS). In its 2021 complete response letter, the FDA challenged the interpretability of this particular scale, bringing its validity and reliability into question. Zevra was able to iron out these issues, returning to the FDA with a rescored scale for the primary endpoint and more results from its own study undertaken in December 2023.

This time, Miplyffa’s efficacy was demonstrated by the rescored 4-domain Niemann-Pick disease Clinical Severity Scale (R4DNPCCSS) score in the patients who used miglustat as their background treatment. This scale is a measure of Niemann-Pick disease progression that looks at four items that have been identified as being the most relevant: ambulation, speech, swallowing, and fine motor skills.

Miplyffa’s approval was ultimately based on a 12-month study in Niemann-Pick disease patients aged two to 19 years, in which 78% of patients also received J&J’s Zavesca, which is marketed in the U.S. for certain patients with Gaucher disease and is used off-label to treat patients with Niemann-Pack disease. Compared to placebo, Miplyffa plus Zavesca halted disease progression through 12 months of treatment as shown by a 0.2 point decrease from baseline on the R4DNPCCSS. By comparison, patients in the trial’s control arm saw 1.9 points of progression on the scale.

Miplyffa must be taken three times a day by mouth in combination with Zavesca. The FDA said that its prescribing information contains a warning for hypersensitivity reactions including hives and swelling under the skin. The drug actually works by boosting the activity of two proteins in the cell called transcription factors EB and E3, which upregulated genes encoding proteins that help lipids within cells return to normal and healthy levels. 

There are, however, some slight doubts over just how effective the drug might be. Its FDA approval comes after outside experts voted 11 to 5 in favor of it at an advisory committee meeting in August. The experts who voted in favor of approval said that they believed the clinical trial data and patient testimonies showed the drug may stabilize the disease, and in some cases improve symptoms, but that the treatment was not dramatically effective.

At the time of the approval, Zevra said that it expected Miplyffa to hit the market in eight to 12 weeks. According to Endpoints, Zevra executives said in a conference call that Miplyffa’s wholesale acquisition cost would range between $40,000 and $106,000 per month, depending on dosage. The company has launched a patient support program to help people obtain the medication. It will include personalized insurance coverage education and support, copay, and alternate funding assistance. 

Two in the space of a week: FDA also approves Aqneursa for Niemann-Pick disease in a potential blow for Miplyffa

Just five days after Miplyffa’s approval, IntraBio jumped in to spoil Zevra’s title as being the only company to have an FDA-approved treatment for Niemann-Pick disease. As the FDA greenlit Aqneursa, it likely dealt a bit of a blow to Zevra, namely because Aqneursa is a standalone therapy – and is, therefore, easier to take than a combination treatment – and is already available on the market. 

Aqneursa’s approval was based on data from a phase 3 trial containing 60 participants that looked at the drug’s effect on neurological symptoms and functioning in adults and children over the age of four with a confirmed Niemann-Pick disease diagnosis. The trial met its primary efficacy endpoint and every secondary endpoint across all patient cohorts receiving Aqneursa, demonstrating “significantly” improved neurological signs and symptoms of the disease and led to functional benefits within 12 weeks. 

For the primary endpoint, Aqneursa achieved a “clinically meaningful” 1.37 point reduction on the Scale for the Assessment and Rating of Ataxia (SARA) score at 12 weeks versus placebo. SARA measures a patient’s level of muscle control when doing activities like walking, sitting, and standing in place. 

IntraBio’s oral monotherapy is a modified amino acid drug indicated for both adults and children weighing at least 15kg, to be taken up to three times a day. It works by targeting and correcting the genetic mutations responsible for Niemann-Pick disease type C, helping to reduce lipid accumulation in cells and slow disease progression.

Similar to Zevra, IntraBio is helping patients access the treatment by launching a support program that will include financial support to “reduce or eliminate” out-of-pocket costs for qualifying patients as well as connect them with third-party resources. It will also feature educational resources and a team of disease specialists.

The push to develop drugs for rare diseases 

Janet Maynard, director of CDER’s Office of Rare Diseases, Pediatrics, Urologic, and Reproductive Medicine, said in a press release that these back-to-back approvals for Niemann-Pick disease treatments reflect the FDA’s “commitment to support development of new treatments for rare diseases.”  

Indeed, the FDA does seem keen to encourage the development of drugs for rare diseases. Just recently, the agency initiated the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) pilot program to help accelerate the development of novel drugs and biologics for rare diseases. Selected participants for the program have access to frequent advice from FDA staff to address product-specific development issues, including clinical study design, choice of control group, and fine-tuning the choice of patient population. The hope is that these increased interactions can address early development issues that may otherwise delay or prevent a promising novel product from progressing to the pivotal clinical trial stage.

Parent advocacy can also be instrumental in the push to develop drugs for rare diseases. In the case of Niemann-Pick disease, there had been years of parental advocacy to push forward experimental drugs before these recent approvals finally came about. 

And we may even see a third drug on its way soon. Dutch company Azafaros is taking its candidate into phase 3 trials next year in patients with either GM2 gangliosidosis or Niemann-Pick disease, offering even more hope to patients suffering from this fatal rare disease.