Hope for Niemann-Pick type C in FDA’s dual drug approval

Niemann-Pick disease type C (NPC) is a rare and progressive neurodegenerative disorder that affects young kids, making it hard for them to swallow, speak, move, and even think (1). Therapeutic options for NPC had been extremely limited until this fall when the Food and Drug Administration (FDA) approved two new drugs for NPC. These approvals mark a significant milestone — offering new hope to patients and families affected by this debilitating condition — but leave open questions about how the drugs will interact if taken together.

NPC is a genetic disorder involving mutations in the NPC1 or NPC2 genes. These mutations inhibit the body from transporting cholesterol and other lipids inside cells. This dysfunction leads to the accumulation of lipids within cells, particularly in the brain, liver, and spleen (2). Most NPC patients only live to about 13 years old.

Until now, there were no FDA-approved drugs for NPC. Clinicians give people with NPC the Gaucher's disease drug, miglustat, which reduces the production of certain types of lipids, but miglustat only slows symptom progression; it does not improve it.

While the exact mechanism of the two newly approved drugs remains enigmatic, researchers have hypotheses as to how they work. The first drug, Miplyffa, works by improving lysosomal function to help clear accumulated lipids from cells, and the FDA approved its use in combination with miglustat. The second drug, Aqneursa, is a modified amino acid that targets the cell’s mitochondria. Lipid buildup can disrupt mitochondrial function, and Aqneursa crosses the blood-brain barrier where it is thought to help restore mitochondrial function.

Obviously, we hope for some sort of complete cure, but these bridges of treatments that slow down the progression of these diseases or even improve symptoms give us more and more time.
- Natasha Shur, Children’s National Hospital

In two double-blind, placebo-controlled studies involving a total of 110 participants, the two drugs showed promising results. Miplyffa slowed disease progression with respect to speech, swallowing, and fine motor skills (3). Participants using Aqneursa showed better outcomes than placebo with regard to gait, sitting, stance and speech (4). While neither drug alone cures NPC, both improved NPC symptoms. The trials did not identify any significant side effects, but clinicians will still carefully monitor for possible side effects, such as kidney and liver function deterioration, to ensure patient safety during treatment.

Although researchers have not yet established how these drugs interact, Natasha Shur, a medical geneticist at Children’s National Hospital, feels comfortable combining them in treatment settings for now. “With such a severe, progressive disease, it's okay to really go forward with multiple therapeutic approaches,” said Shur. “That is actually similar for how we're approaching a lot of rare diseases when there's not one quick cure.”

Because so few people have NPC, conducting thorough research on treatments — especially combination treatments — is a challenge. Andrés Klein, a geneticist at the University for Development in Chile, noted that there is no data on the combined treatment even in animal models. He added, “The beauty is that every drug, at least in principle, is working at different levels, so that's why it makes sense to test the three drugs combined.”

The approvals are also a testament to the power of the NPC community — including patients, families, and advocacy groups — in driving research forward.

“When people who have a rare disease really rally together, along with the medical community, there's advocacy, and that does lead to more research and development,” said Shur. “If we can do this for Niemann-Pick type C and have more options, then we can do this for every rare disease. And some of these medications we've uncovered for Niemann-Pick probably do have potential in other rare diseases as well.”

Moreover, insights gained from NPC research may have broader implications for more common neurological conditions, said Klein. “Although NPC is rare, it shares a lot of histopathological features with Alzheimer's. … My guess is that the therapies that are working for NPC could be repurposed to Alzheimer's.”

With respect to NPC, Shur feels hopeful about the effect these two new approvals will have. “Obviously, we hope for some sort of complete cure, but these bridges of treatments that slow down the progression of these diseases or even improve symptoms give us more and more time,” said Shur. “Every day matters for these beautiful kids.”

References