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Orphazyme A/S. (1/30/19). "Press Release: Orphazyme Reports Positive Results from Full Data Set of Phase II/III Arimoclomol Tria in Niemann-Pick Disease Type C (NPC)". Copenhagen.

Organisations Organisation Orphazyme A/S (Nasdaq Copenhagen: ORPHA.CO)
  Group Orphazyme (Group)
  Organisation 2 FDA (US Food and Drug Administration)
  Group United States (govt)
Products Product arimoclomol
  Product 2 clinical research
Person Person Hinsby, Anders (Orphazyme 201003– CEO + co-founder before BankInvest Biomedical Venture)

> Primary endpoint shows 74% reduction in disease progression after 12 months compared to placebo control (p-value =0.0506)

> Biomarker results demonstrate statistically significant biological response to treatment

> Orphazyme to engage with FDA and EMA on path to approval while preparing for filing

Orphazyme A/S, a biopharmaceutical company dedicated to developing treatments for patients living with rare diseases, today announced the full data set for its Phase II/III clinical trial of arimoclomol in NPC, a devastating rare genetic disorder. Treatment with arimoclomol adjunct to routine clinical care resulted in a 74% reduction in disease progression (p-value =0.0506) as measured by the primary endpoint, 5-domain NPC Clinical Severity Scale (NPC-CSS). In the predefined subgroup of patients of 4 years and older (44 out of 50 randomized patients in the trial), the treatment difference was statistically significant with a minimal disease progression at month 12 in the arimoclomol-treated group (p-value =0.0219). A highly statistically significant treatment difference was observed in another predefined subgroup analysis, requested by the European Medicines Agency (EMA), that compared arimoclomol to placebo control in patients receiving miglustat as a part of routine clinical care (p-value =0.0071).

In agreement with the US Food and Drug Administration (FDA), treatment response defined as no change or improved on the Clinical Global Impression of Improvement scale (CGI-I) was included as a co-primary endpoint. A responder rate of more than 50% in the placebo control group impeded the ability to show an overall effect on this endpoint. However, when considering patients who severely progressed during the trial, only 10.7% of the arimoclomol-treated patients got ‘much worse’ or ‘very much worse’ compared to 26.7% in the placebo control group.

Anders Hinsby, Chief Executive Officer of Orphazyme, said: "With this highly compelling data set, we are looking forward to working with regulatory authorities to make arimoclomol available to patients as fast as possible. It has been inspirational to collaborate with the NPC community on this journey and I wish to thank the families for their dedication and patience. Moreover, the positive results from this trial further strengthen our confidence in heat-shock protein amplification as a potential treatment for a range of protein-misfolding diseases.”

Karl-Eugen Mengel, Principal Investigator, Mainz University Hospital, said: “I am very happy for the patients that may now benefit from our efforts to change the course of this debilitating disease. Achieving such a clinically meaningful response to treatment in this Phase II/III trial with efficacy results for NPC is promising”.

Several exploratory biomarkers were measured during the trial, demonstrating a clear biological effect of arimoclomol in support of the clinical results. The biomarker data showed a biological response to arimoclomol on key characteristics of its mechanism of action and the disease biology of NPC. This includes the important rescue protein HSP70 and accumulating lipids involved in the disease pathology. HSP70 levels showed a statistically significant increase in patients treated with arimoclomol (p-value =0.0005) demonstrating target engagement. In addition, arimoclomol treatment also led to statistically significant reductions in the accumulation of disease-related lipids such as unesterified cholesterol in skin and blood cells (p-value =0.0450). Furthermore a reduction of the cholesterol metabolite oxysterol was also observed (p-value =0.0613).

As previously reported, overall, baseline characteristics were well-balanced across treatment arms. Arimoclomol was well-tolerated with a similar incidence of adverse events (AEs) for arimoclomol (88.2%) and placebo control (81.3%). Serious AEs occurred less frequently in the arimoclomol group (14.7%) compared to placebo control (37.5%).

The secondary endpoints, NPC Clinical Database (NPC-CDB), Scale for Assessment of Rating of Ataxia (SARA), 9-Hole Peg Test (9HPT), and EQ-5D-Y, did not statistically support a benefit of the arimoclomol group over the placebo control group, albeit directional benefit was observed in the NPC-CDB and the 9HPT assessments. The lack of effect may indicate that these endpoints may not have been appropriate to demonstrate an effect in this patient population over the relatively short 12-month treatment period. Post-hoc analyses are on-going to further the understanding of these results.

Orphazyme understands the urgency of making arimoclomol available to NPC patients as soon as possible. We will immediately initiate filing preparations and seek to meet with the FDA and EMA mid-2019 to discuss the path to approval.

24-month data is expected to become available from the on-going open-label extension of the trial in Q3 2019. Orphazyme plans for submission of filing in the US and EU in H1 2020, with potential approval in H2 2020.

Reported impact of arimoclomol Phase II/III trial on outcome measures

Outcome measures Arimoclomol p-values
Primary endpoints
Mean change from baseline on Arimoclomol: 0.5 pts 0.0506
5-domain-NPC-CSS (primary) Placebo control: 1.9 pts
Difference: -1.34 pts
Treatment response defined as no change Arimoclomol: 58.8% 1.0000
or improvement on CGI-I (co-primary in US) Placebo control: 56.3%
Difference: 2.5%

Predefined subgroup analyses 5-domain-NPC-CSS

Mean change from baseline on Arimoclomol: 0.1 pts 0.0219
5-domain-NPC-CSS (patients = 4 years) Placebo control: 2.1 pts
Difference: -1.68 pts

Mean change from baseline on 5-domain Arimoclomol: -0.2 pts 0.0071
-NPC-CSS (miglustat is part of routine Placebo control: 1.8 pts
clinical care) Difference: -2.00 pts

Predefined sensitivity analyses 5-domain-NPC-CSS

Multiple imputations (MMRM) Treatment difference: 0.0587
-1.24 pts
Additional covariate: Age at study entry Treatment difference: 0.0602
-1.29 pts
Additional covariate: Age at first Treatment difference: 0.0479
neurological symptoms -1.34 pts
Non-parametric analysis Arimoclomol: 0.00 pts 0.1966
Placebo control: 1.00 pts
Difference: -1.00 pts

Exploratory biomarker endpoints

Change in HSP70 level 1815.0 pg/mL 0.0005
Change in unesterified cholesterol -53433 ng/mg 0.0450
level in blood cells
Change in cholesterol metabolite -8.0579 ng/mL 0.0613

Safety & tolerability

Adverse events Arimoclomol: 88.2%
(3 discontinuations)
Placebo control: 81.3%
Serious adverse events Arimoclomol: 14.7%
Placebo control: 37.5%

Analysis of the full data set confirms the top-line results announcement (no. 12-2018) on September 28, 2018, while strengthening the significance of the trial results.

This company announcement does not impact the 2018 financial guidance.

About the trial

The trial was a multi-center, prospective, double-blinded, placebo-controlled interventional study with a 12-month duration. In total, 50 patients between the age of 2-18, randomized 2:1 to arimoclomol or placebo control, were enrolled in the US and EU. The purpose of the trial was to assess the efficacy and safety of arimoclomol, compared to placebo control, in the treatment of NPC, administered in addition to the patient's rountine clinical care. The primary endpoints, 5-domain NPC-CSS and CGI-I (in the US), evaluated the treatment difference between the arimoclomol-treated and the placebo control group after 12 months of treatment.

Conference call

Orphazyme will be hosting an investor call at which Chief Executive Officer, Anders Hinsby, Chief Medical Officer, Thomas Blaettler, and Chief Scientific Officer, Thomas Kirkegaard Jensen, will be presenting the full clinical trial data set for arimoclomol in NPC. The presentation will be followed by a Q&A session.

The call will be held on: Wednesday, January 30, 2019 at 11.00 AM CET.

Dial-in details:
· Denmark: 3272 8042
· France: 01 76 700 794
· Netherlands: 02 07 143 545
· Sweden: 08 50 69 21 80
· United Kingdom: 0844 571 88 92
· United States: 1 631 510 74 95
Event Title: Orphazyme Investor Call
Confirmation code: 8649097

The presentation will also be available via webcast:
After the call, the presentation will be available by using the following dial-in details:
· UK (/international): +44 (0)333 300 97 85
· United States: 1 (917) 677 7532
Confirmation code: 8649097


Phone: (+45) 39 17 82 72
Ole Maaløes Vej 3
DK-2200 Copenhagen N


Phone: (+1) 617-663-5375
275 Grove Street
Suite 2-400
Newton, MA 02466

Record changed: 2023-06-05


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