June 25, 2024

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Heat shock response inducer Miplyffa suffers regulatory setback in US and EU

Heat shock response inducer Miplyffa suffers regulatory setback in US and EU


Heat shock response inducer Miplyffa suffers regulatory setback in US and EU. 

Danish biopharmaceutical company Orphazyme A/S has announced an update on the regulatory review of its drug candidate Miplyffa (arimoclomol) in the European Union.

The company said that while Orphazyme was encouraged by the positive feedback from the ex post panel meeting held on February 17, 2022, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) notified Orphazyme: Marketing Authorization Application for arimoclomol (MAA) gave a negative trend vote.

The trend vote suggests that the current direction of the CHMP is not to approve arimoclomol when it meets at the end of March 2022. Orphazyme believes this position of the CHMP is unlikely to change until a formal vote next month.



Heat shock response inducer Miplyffa suffers regulatory setback in US and EU



This means that arimoclomol has suffered setbacks in both US and EU regulation.

In June 2021, the US FDA sent a Complete Response Letter (CRL) to the New Drug Application (NDA) for Miplyffa (arimoclomol). NPC is a devastating and often fatal disease for which there is no approved treatment in the United States.


arimoclomol is a first-in-class heat shock protein (HSP) amplifier that amplifies the production of HSPs that rescue defective misfolded proteins and improve lysosomal function.

Arimoclomol was developed for the treatment of type C Niemann-Pick disease (NPC) and is currently being studied in 10 Phase 1, 4 Phase 2 and 3 pivotal Phase 2/3 trials. arimoclomol has been granted orphan drug designation (ODD) for the treatment of NPC in the United States and the European Union.

In addition, the FDA has granted Fast Track Designation (FTD), Breakthrough Drug Designation (BTD), and Rare Pediatric Disease Designation (RPDD) to arimoclomol for the treatment of NPC.


In this statement of the EU regulatory update, Orphazyme did not disclose the reason for the negative trend vote by the CHMP.

However, in a statement issued last year, Orphazyme pointed out that the US FDA issued the CRL based on the need for more qualitative and quantitative evidence to further confirm the validity of the 5-domain NPC Clinical Severity Scale (NPCCSS) and explanations, especially the swallowing domain.

In addition, the FDA noted in the CRL that additional data is needed to support the benefit-risk assessment of NDAs beyond a single Phase 2/3 clinical trial.

The primary endpoint of the Phase 2/3 clinical trial was disease severity progression as measured by the 5-domain NPCCS. This is a disease-specific measure of disease progression consisting of five domains that are most clinically relevant to NPC patients, caregivers, and physicians.


Arimoclomol is Orphazyme’s lead compound, a small molecule heat shock stress inducer that amplifies the production of heat shock proteins (HSPs).

The heat shock response is a protective system responsible for handling cellular stress and is involved in maintaining proper protein folding.

HSP can rescue defective misfolded proteins, clear protein aggregates, and improve lysosomes function.


Arimoclomol can be rapidly dispersed throughout the body after oral administration, and can cross the blood-brain barrier and enter the brain.

The drug works in stressed cells by stimulating the cell’s own heat shock response, helping misfolded proteins to restore normal function, or using the cell’s recycling system, the lysosome, to recycle these proteins when normal function cannot be restored.

Stopping toxic aggregates from forming would help reduce the buildup of misfolded proteins that can be responsible for a variety of diseases and symptoms.


Currently, arimoclomol is being developed as a potential therapy for the treatment of 4 rare diseases, including: 2 lysosomal storage disorders (Niemann-Pick disease type C [NPC] and Gaucher disease [GD]) and 2 neuromuscular diseases (sporadic inclusion body myositis [sIBM], amyotrophic lateral sclerosis [ALS]). The drug has been studied in 10 Phase 1, 4 Phase 2, and 3 pivotal Phase 2/3 clinical trials.


Niemann-Pick disease type C (NPC) is an inherited, progressive, debilitating, and often fatal neurovisceral disease.

The disease belongs to a family known as lysosomal storage diseases and is caused by mutations that cause defects in NPC proteins.

Consequently, lipids normally cleared by lysosomes accumulate in tissues and organs, including the brain, and drive disease pathology.

In the United States and Europe, the number of people with NPC is estimated at 1800.


NPC is a devastating disease and there is an urgent need for disease-modifying therapy (DMT). There are no approved treatments for NPC in the United States.

If approved, arimoclomol would be the first drug to treat NPC in the United States.

In Europe, Zavesca (miglustat) was approved in 2009 as the only drug for the treatment of NPC. 


Data from the pivotal Phase 2/3 randomized placebo-controlled trial (CT-ORZY-NPC-002) suggest that arimoclomol has a positive effect in stabilizing neurological progression in NPC, particularly in the subgroup of patients ≥4 years of age and those receiving miglustat (Meglustat). statista) in a subgroup of patients who were routinely cared for.

Arimoclomol showed sustained improvement in disease progression during 2 years of treatment.

In addition, patients initially randomized to receive placebo experienced a 90% reduction in disease progression after switching to arimoclomol.


Arimoclomol has been shown to have clinically meaningful effects on disease progression in NPC, which is further supported by a biomarker effect that suggests an impact on the biological basis of the disease, and has a favorable safety and tolerability profile.






Orphazyme announces update on regulatory review of arimoclomol in the European Union

Heat shock response inducer Miplyffa suffers regulatory setback in US and EU

(source:internet, reference only)

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