Orphazyme’s arimoclomol will likely be used alongside Johnson & Johnson’s Zavesca (miglustat) for most children with Niemann-Pick disease type C (NPC) following a probable FDA approval, experts said.

Though an approval would make arimoclomol the only FDA-approved NPC treatment, current off-label use of Zavesca will likely continue as US payers have covered it for NPC considering its link to improved survival, experts said. In addition, since results from the Phase II/III BLANK trial, which allowed patients to continue on standard of care (SOC), showed greater efficacy among patients taking both Zavesca and arimoclomol, payers will be more likely to allow both treatments in tandem, one expert said.

Though the Phase II/III study did not reach statistical significance in either of its primary endpoints, experts say strong statistical significance in multiple reasonable posthoc analyses, including one predetermined by the FDA, bolster its regulatory chances. Arimoclomol has a PDUFA date of 17 June.

Experts said there is no biological reason to believe that arimoclomol’s mechanism of action (MOA) of restoring misfolded protein would work in the uncommon form of NPC with double null mutations where no protein is made, meaning a label will likely exclude them. In addition, the lack of any FDA-approved NPC treatment, as well as biomarker data suggesting arimoclomol is effective at increasing heat shock proteins (HSPs), makes an FDA approval a strong bet, they added. Analyst reports have also predicted approval.

Arimoclomol is also available to NPC patients in an ongoing Phase III early access study. The drug has estimated worldwide sales of $340m, and Orphazyme has a market cap of $382m. NPC is a rare genetic lysosomal storage disease where the body cannot properly transport cholesterol and lipids inside of cells, leading to their accumulation within the brain and other tissues throughout the body. Orphazyme did not respond to a request for comment prior to publication.

Arimoclomol likely to complement – not replace – growing Zavesca use

Clinical evidence suggests that arimoclomol reduces disease severity and biomarkers indicate the drug upregulates targeted proteins, said Stephen Sturley, PhD, professor, Department of Biology, Barnard College, New York. While FDA decisions in rare diseases with no prior approvals are tough to predict, those two datapoints give arimoclomol a solid chance at an approval, he added.

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In the 50-patient Phase II/III study, patients had a 1.34-point reduction in NPC composite clinical severity (NPC-CSS) score (p=0.0537), which experts agreed is a clinically meaningful indicator of disease progression. However, in a prespecified posthoc analysis of the subgroup of patients taking Zavesca, the 39 patients taking Zavesca had a 2.01-point reduction in NPC-CSS (p=0.0074). This clinical evidence suggests arimoclomol works better with Zavesca, said Dr Elizabeth Berry-Kravis, paediatric neurologist, Rush Paediatric Specialty Care, Chicago, Illinois. By increasing production of HSPs, arimoclomol could correct misfolded proteins and improve the function of lysosomes in patients with NPC.

Arimoclomol acts by partially preventing mutations in affected proteins, which differs from Zavesca’s MOA of removing toxic lipids at the level of synthesis, said Andrew Munkacsi, PhD, assistant professor, Centre for Biodiscovery, Victoria University of Wellington, New Zealand. The distinct MOAs mean the two treatments could work synergistically with no apparent concerns of adverse interactions, he explained. Moreover, recently published natural history data linking single-agent Zavesca to improved survival in NPC makes it likely for insurance carriers to cover both treatments first-line if arimoclomol is approved, Berry-Kravis added. A 789-patient retrospective analysis, drawing data from five national cohorts and from the NPC Registry, linked Zavesca use in NPC to a median survival improvement of 10 years from onset of neurological manifestations and of 5 years from NPC diagnosis. (Patterson et al., J Inherit Metab Dis. 2020;43(5):1060-1069).

Zavesca is approved for NPC in many major markets, including the European Union, Canada and Japan. Though not approved for NPC, it is FDA-approved for Gaucher’s disease and is commonly used off-label to treat NPC, experts said. The timing of arimoclomol’s approval aligns with an increasing trend toward Zavesca use in most newly diagnosed patients with NPC and a steady decrease in payer resistance to allow its off-label use, they added.

By sending insurance providers a copy of the Patterson and colleagues publication, most US payers will now cover Zavesca immediately or after only one appeal, Berry-Kravis said. Previously, Berry-Kravis explained, insurance would typically reject appeals for Zavesca coverage four to six times before ultimately covering the treatment.

Though an estimated 50% of US patients with NPC use Zavesca, upwards of 70–80% of patients diagnosed within the past year are taking the drug, Berry-Kravis said. Except for some uncommon cases where tolerability due to diarrhoea or stomach pain is an issue, most clinicians in the US prescribe Zavesca, Sturley agreed. Though some clinicians with minimal NPC experience may only prescribe arimoclomol, provided it becomes the first FDA-approved treatment, almost all specialty treatment centres – where most newly diagnosed patients with NPC are seen – will look to prescribe both, Berry-Kravis explained.

Still, one NPC researcher cautioned the available data – one-year clinical results with a year of follow-up and no extensive tissue biomarker data – is not enough to convince clinicians of arimoclomol’s efficacy. Nevertheless, the researcher said physicians would want to prescribe arimoclomol because few treatment options are available, and a seemingly clean safety profile limits its risk. In the Phase II/III study, adverse events occurred in 85.7% of arimoclomol patients and 81.3% of placebo patients, while serious adverse events occurred in 14.3% of arimoclomol patients and 37.5% of placebo patients, according to a September 2018 company press release. Still, continued use is necessary to gain the requisite study data needed to determine efficacy on the longer-term outcomes that are important to physicians, the researcher added.

Better scales, biomarker data improve regulatory chances

Over time, evolving metrics for determining NPC disease progression add some uncertainty to how the FDA judges approval in this rare disease, Munkacsi said. Nevertheless, blood biomarkers, including higher levels of HSP70 (a change of 1815.0 pg/mL (p=0.0005)) and decreased accumulation of unesterified cholesterol level in blood cells (change of -53433 ng/mg (p=0.0450)) make a strong case to the FDA that arimoclomol is achieving its target of upregulating heat shock proteins, Munkacsi and Sturley agreed.

In addition, the NPC-CSS scale, which was developed after the FDA rejected Zavesca’s bid for NPC approval in 2010, is more sensitive to detecting improvement in NPC than the more subjective scales available in 2010, Sturley added. As a result, the positive trends in NPC-CSS seen in this trial give arimoclomol a much better chance of approval than Zavesca had, he explained.

Furthermore, if the three patients with a double null mutation of both the NPC1 and NPC2 genes are removed from the dataset, the improvement in disease outcomes become highly statistically significant, bolstering regulatory chances, Berry-Kravis said. In the 47 patients without the double null mutation, there was a 1.56-point reduction in NPC-CSS (p=0.0024). Because there is no reason to believe arimoclomol would work for this uncommon form of NPC where no protein is produced at all, any FDA label is likely to reflect this, Berry-Kravis explained.

William Newton is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.