Clinical trials

Orphazyme is developing arimoclomol in four indications. Orphazyme has fully recruited a Phase II/III trial in NPC (trial results expected Q3 2018), initiated a Phase II/III trial in sIBM in August 2017 and plans to start a Phase II/III trial in ALS in Q3 2018.

In addition, a Phase II Proof-of-Concept trial in Gaucher disease was initiated in Q2 2018. If positive, all three Phase II/III trials are intended to form basis for a single study filing in each respective indication.

The company expects to have completed all three Phase II/III trials by the end of 2020, with the first potential marketing authorization in 2020.

Arimoclomol Program

    Protein-aggregation diseases

  • sIBM
    A Phase II/III trial was initiated in August 2017 in the USA and Europe to establish efficacy and is intended to form the basis for registration. Orphazyme conducts the trial in collaboration with the University of Kansas and the University College London.

    The trial is a randomized, double-blinded, placebo-controlled Phase II/III trial assessing efficacy and safety of arimoclomol 400 mg three times a day in patients with sIBM. The primary endpoint analysis is after 12 months, while the trial duration will continue for up to 20 months. 150 patients (75 per arm) will be enrolled, randomized 1:1 to receive arimoclomol or placebo. The primary efficacy endpoint will be the change from baseline to 12 months in the IBMFRS total score. Secondary endpoints include the change from baseline to month 20 in the IBMFRS sum score (durability of treatment) and changes from baseline to month 12 and 20 in different measures of strength and function.

    The average changes in these outcomes will be compared between placebo and arimoclomol at 12 and 20 months, respectively. Results from the Phase II/III trial are expected in H1 2020.
  • ALS
    Based on the mechanism of action of arimoclomol that is expected to be relevant across the broad ALS patient population, the results in the Phase II SOD1 ALS trial trend effect observed in the open label portion of the Phase II trial in sporadic ALS and encouraging feedback from FDA, Orphazyme is working on a Phase II/III trial design intended to support a marketing authorization in the broad ALS population. The Company is currently evaluating a design that will include clinical and genetic enrichment strategies to ensure homogeneous disease progression in the trial.

    The next step is to finalize the protocol for submission to EMA for scientific advice prior to enrolling patients in the trial. Expectedly, the trial will be a randomized, double-blinded, placebo-controlled Phase II/III trial assessing efficacy and safety of arimoclomol 400 mg three times a day. The trial is expected to enrol approximately 200-300 patients and is planned to start in Q3 2018 and results are expected in H2 2020.
  • Lysosomal storage diseases

  • NPC
    Patients are randomized 2:1 to arimoclomol and placebo, respectively, and assessed for a total of 12 months of randomized treatment, followed by open-label treatment of up to 24 months. The purpose of the trial is to assess the efficacy and safety of arimoclomol when administered in addition to patient’s current prescribed best standard of care. The trial was fully enrolled in Q2 2017 and trial completion is expected in H2 2018. The primary endpoint is disease severity as measured by the NPC clinical severity score.

    Contingent on positive results of the trial, Orphazyme expects to file an NDA (US) and MAA (EU) in H2 2019 with potential approval in H1 2020.
  • Gaucher disease
    Patients are to be randomized 1:1:1:1 into four treatment arms – active treatment at three different doses and placebo, and assessed for six months. Following the placebo-controlled period, the placebo group will be re-randomized into one of the three active treatment groups for a six-month extension.

    The primary endpoint in this trial is chitotriosidase levels in CSF and blood. Chitotriosidase is a known marker of Gaucher disease, because it is found in high levels in patients whose immune cells have accumulated an excess lipid burden.

    The Phase II clinical trial, is anticipated to start in Q2 2018.

New Molecular Entities Program

  • NME
    Orphazyme is developing a new series of HSP-amplifying drugs based on its expertise and know-how about the convergences of HSPs, protein aggregation, and cellular recycling systems and how these can be targeted for therapeutic benefit. As of the date hereof, Orphazyme has several leads that constitute potentially new intellectual property opportunities. These molecules are currently being vetted and will be prioritized based on their suitability for specific diseases.

About ALS

Amyotrophic Lateral Sclerosis (ALS), also called Lou Gehrig’s disease, is a rapidly progressive and invariably fatal neurological disease. It attacks neurons responsible for controlling voluntary muscles. ALS results in muscle weakness, progressive disability, and eventually death, typically from respiratory failure. Time from onset to mortality is typically short in the range of two to five years. However, ALS is a distinctly heterogeneous disease and the clinical course is variable, with some patients dying within one year from symptom onset and other living for more than a decade.

Muscle weakness results from progressive degeneration of motor neurons in different parts of the central nervous system, where upper and lower neurons selectively die. The cause of damage to the neurons is unknown, but several theories have been proposed, including glutamate toxicity, protein misfolding, and oxidative stress.

Prevalence for ALS
The incidence of ALS is estimated at between 1-3 per 100,000 individuals per year globally. The patient population in the USA and Europe is estimated to be approximately 50,000 patients. In Japan, it is estimated that there are between 8,000-14,000 patients with ALS.



About sIBM

Sporadic Inclusion Body Myositis (sIBM) is an acquired, rare, and slowly progressing muscle disorder which becomes apparent during adulthood. Among individuals older than 50 years it is the most common muscle-wasting disorder. The disease is generally characterized by progressive weakness and degeneration (atrophy) of the muscles, especially those of the arms and legs, particularly in the quadriceps. sIBM typically affects the ability to grab or manipulate objects, causes trouble walking or rising, and can progress to cause severe disability. In addition, difficulty swallowing (dysphagia) due to weakness of throat muscles may occur. sIBM typically presents itself later in life with 87% of patients experiencing onset of symptoms at 50 years of age or more, and earlier symptoms usually only being recognized retrospectively. In most cases, the progression is slow and progresses over the next 10 to 15 years until the affected patient has lost mobility entirely. 

Prevalence for sIBM
The size of the patient population in the USA and Europe is not fully elucidated, but a 2017 publication estimated a patient population of approximately 24.8 and 45.6 per million or at least 17,000-31,000 individuals in the USA and the major European countries



About NPC

Niemann-Pick disease Type C (NPC) is a rare, genetic, and progressive disease that impairs the ability of the body to move cholesterol and other fatty substances (lipids) inside the cells. The result is an accumulation of lipids within the body’s tissue, including the brain tissue, causing damage to the affected areas. The symptoms upon onset of NPC vary from fatality during the first months after birth to a progressive disorder not diagnosed until adulthood. The disease affects neurologic and psychiatric functions as well as various internal organs. NPC is usually fatal and the majority of individuals with the disease die before the age of 20. Adults diagnosed with NPC are more likely to present with dementia or psychiatric symptoms. 

Prevalence for NPC
NPC often presents in childhood but can present at any age. The incidence of the disease is estimated to be 1 in 120,000 births and it is estimated that the NPC patient population is between 1,000-2,000 in the USA and Europe.



About Gaucher DISEASE

Gaucher disease is a rare, inherited metabolic disorder causing certain sugar (glucose) containing fat (lipids and especially glycolipids) to abnormally accumulate in the lysosomes of cells, especially within the bone marrow, spleen, and liver, due to the lack of a certain enzyme (glucocerebrosidase). The symptoms vary greatly from patient to patient with some patients having few or no symptoms while others may experience significant complications. The usual symptoms of Gaucher disease include an abnormally enlarged liver and/or spleen (hepatosplenomegaly), low levels of circulating red blood cells (anemia), and blood cells promoting clotting (thrombocytopenia) and skeletal abnormalities. Like NPC, Gaucher disease is an autosomal recessive disorder. 

Prevalence for Gaucher disease
The total number of Gaucher patients in the USA and Europe is conservatively estimated at 10,000-15,000 individuals. Of the total market, Orphazyme focuses on the 10-30% with neuropathic Gaucher disease, where no treatments are available today.


Arimoclomol’s MECHANISM of Action

The production of HSPs is regulated by a transcription factor, heat shock factor 1 (“HSF1”). A transcription factor is a protein that regulates production of other proteins in the cell. In the case of HSF1, the proteins being regulated are HSPs. Activation of HSF1 starts the production of the major stress-inducible HSP70-chaperone along with other HSP-chaperones, which help reshape the cells’ misfolded proteins and take care of the recycling systems. Under normal cellular conditions, HSF1 is inactive. However, the transcription factor can be activated by an initial cellular stress, such as protein misfolding, and becomes fully activated under a sustained stress signal.

Arimoclomol amplifies and prolongs the activated, HSP-producing state of HSF1. This leads to an amplification in the production of cell protective HSPs, but only in physiologically stressed cells. 


Clinical profile and uses of arimoclomol

The clinical experience with arimoclomol supports its continued development. 


As of the date hereof, no safety risks from taking arimoclomol have been identified in seven Phase I trials and three Phase II trials, and, overall, tolerability of arimoclomol (i.e. the degree to which an overt adverse effect can be tolerated by the subject/patient) was comparable to a placebo. 


Arimoclomol is orally administered and has a bioavailability of 80-90%. High bioavailability reduces the amount of drug administered while achieving the desired pharmacological effect.

In addition, arimoclomol readily crosses the blood-brain barrier. The blood-brain barrier is a selectively permeable membrane which prevents large compounds from entering the cerebrospinal fluid (“CSF”) (liquid surrounding the brain and spinal column). Arimoclomol reaches CSF drug concentrations comparable to the concentration found in circulating blood. Good brain penetrance is key to treatment of many central neurological diseases.


Arimoclomol has achieved a clinical proof-of-concept in ALS (1) and sIBM (1). Phase II trials in both indications have shown consistent trends of clinically relevant efficacy in pre-defined analyses.


(1) Clinical proof-of-concept in ALS and sIBM achieved by demonstrating benefit across efficacy endpoints and assessments as compiled evidence, also in absence of statistical significance.