Wilson Disease: New Treatment Paradigm on the Horizon?

Wilson Disease Overview

Wilson disease is a monogenic, autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the ATP7B gene that result in reduced or absent ATP7B protein activity. ATP7B plays a role in maintaining copper homeostasis in the liver via both biliary excretion of excess copper and synthesis of functional ceruloplasmin by delivering copper to the trans-Golgi network. Functional ceruloplasmin (holoceruloplasmin) contains six copper atoms per molecule and once synthesized is released by the liver and safely transports copper to tissues throughout the body that require it. In Wilson disease no copper atoms are incorporated into the ceruloplasmin (apoceruloplasmin) while there is also an inability to dispose of excess copper via biliary excretion that leads to accumulation in the liver. Hepatic copper accumulation results in liver injury characterized by inflammation, fibrosis, and apoptosis of hepatocytes and causes non-ceruloplasmin-bound copper to be released into the bloodstream. This free copper is taken up by tissues throughout the body, accumulating in other organs and causing the non-hepatic manifestations of the disease, with the most common being neurological symptoms.

Clinical presentation of Wilson disease is somewhat varied with the age at which symptoms first present having been observed as early adolescence and as late as 50-70 years of age. Symptoms typically begin in the teenage years or twenties and commonly include fatigue and jaundice as well as tremor, dystonia, ataxia, and parkinsonism. Diagnosis is made utilizing tests that include measurements of serum ceruloplasmin, 24 hour urinary copper excretion, hepatic copper and non-ceruloplasmin-bound copper in addition to identification of Kayser-Fleischer rings, which are dark rings of copper deposits that encircle the iris, via an eye exam. More recently, genetic testing for mutations in the ATP7B gene has also been incorporated into the process of diagnosis. If left untreated the disease is fatal but with currently available treatments patients may be able to have a normal lifespan assuming lifelong compliance.   

Current Standard of Care

The current treatment paradigm for Wilson disease has been largely unchanged for decades and includes chelators, which increase excretion of copper, and zinc, which decreases uptake of copper from the digestive tract. Chelators include d-penicillamine (DPA), which has been used in patients since 1956 and trientine (TETA), introduced in 1969 as a second-line treatment for those who are intolerant of d-penicillamine. These chelators may used alone or in some severe cases in combination with zinc for 2-6 months to normalize copper levels with a lower dose of a chelator or zinc monotherapy used after normalization as a maintenance therapy. Adverse events associated with DPA that include sensitivity reactions, lupus like syndrome, bone marrow toxicity and renal toxicity result in an approximately 30% discontinuation rate.  While TETA is better tolerated with discontinuation rates in range of 5-10% due to adverse events including hypersensitivity reactions, anemia and renal toxicity both chelators have been reported to cause paradoxical neurological worsening in over 10% of patients.  Reserved for use as maintenance therapy, zinc is generally well tolerated with the most common side effect being gastric irritation that can be dose-limiting in some cases.  As a result, discontinuation rates for zinc are almost zero with the biggest drawback being the slow negative copper balance relative to chelators. Compliance issues for both treatments can also be attributed in part to the requirement that they typically need to be taken three times per day on an empty stomach. Transplantation is curative but is typically reserved for cases of acute liver failure.

ALXN1840 (WTX101)

Stockholm-based Wilson Therapeutics, developer of WTX101 (bis-choline tetrathiomolybdate), was acquired by Alexion Pharmacueticals in April 2018 for approximately $855 million. WTX101, now referred to as AXLN1840, is an oral copper-protein-binding molecule that is currently in a Phase 3 trial. ALXN1840 is proposed to be an improvement over standard of care chelators as a result of its ability to not only act as a chelator in the liver but also pass through the blood-brain barrier to be taken up by neuronal cells and bind to albumin bound copper in the blood to promote clearance. The mechanism of action, illustrated below, is through binding copper with albumin to form a complex that is removed via biliary excretion. 

In a Phase 2 open-label, multicenter study of  ALXN1840 28 patients were enrolled that received 15-60mg/day dose. The maximum dose in the protocol was originally planned to be 300mg but required reduction to 60mg/day maximum after ALT increases were seen in a patient receiving 120mg/day. Enrolled patients were either treatment naïve or had received no more than two years of treatment with zinc or chelators. The primary endpoint was change in non-ceruloplasmin-bound copper corrected for copper bound to an ALXN1840 tripartite complex at 24 weeks with successful treatment defined as either normalized corrected non-ceruloplasmin-bound copper or a reduction of at least 25% from baseline. The investigators elected to subtract non-ceruloplasmin-bound copper that is bound to a tripartite complex due to the contention that it is not part of the toxic copper pool. At week 24 20/28 (71%, p<0.0001) patients achieved treatment success with 16/28 (57%) achieving or maintaining normalized corrected non-ceruloplasmin-bound copper.  Mean corrected non-ceruloplasmin-bound copper decreased by 72% from baseline at week 24 in all patients (p<0.001.) Significant improvements were also seen in the Unified Wilson Disease Rating Scale (UWDRS) parts II and III, which measure patient-reported neurological disease and trained-rater-assessed neurological status respectively.

The most common adverse events were increases in ALT, AST or γ-glutamyltransferase, which were seen in 11/28 (39%) patients with three needing to discontinue treatment as a result of ALT increases between 14.3 and 29.3 times from baseline. Additionally, one patient discontinued treatment due to further neurological decline at week 12 and two patients had treatment discontinued by investigators due to psychiatric or behavioral symptoms that prevented them from following the study protocol. The investigators highlight that no neurological worsening was seen in treatment naïve patients and speculate that ALXN1840 may be an improvement over standard of care due to its ability to bind to copper in the bloodstream and prevent it from entering the CNS. Along with less severe adverse events compared chelators, a more convenient once daily dosing and more rapid normalization of copper levels ALXN1840 may represent a significant improvement over current standard of care. 

After aligning with the FDA and EMA on the design for a single pivotal Phase 3 trial to support approval Wilson Therapeutics initiated the study in February of 2018. This trial enrolled 215 patients randomized to either 15-60mg/day of ALXN1840 or standard of care therapy with a primary outcome measure of copper control, assessed as the percentage change in corrected non-ceruloplasmin-bound copper levels from baseline to 48 weeks. Since the original announcement of the study a number of amendments of have been made.  First, in 2018 Alexion opted to re-power the study to show superiority versus standard of care.  In April of 2019, Alexion updated the primary outcome measure in April of 2019 from non-ceruloplasmin-bound copper corrected for the amount of copper bound to the AXLN1840 tripartite complex to a non-corrected measure. The non-corrected non-ceruloplasmin-bound copper results from the Phase 2 trial do not appear to be disclosed which makes it difficult to determine what the potential impact of this endpoint change would have been. Finally, in the third quarter of 2020 at their investor day Alexion disclosed that they were in discussions with regulators regarding designing and validating a new endpoint using a biomarker of labile bound copper that the company asserts is the first direct measure of loosely bound biologically active copper. To support this biomarker Alexion is running two additional studies, a balance study to assess copper mobilization and elimination to confirm biliary tract excretion, and a liver biopsy program to show the de-coppering ability of ALXN1840. During their Q1 2021 earnings presentation the company confirmed that topline data would be delayed from 1H 2021 to Q3 2021 as a result of the revised endpoints. These significant changes make it somewhat difficult to envision how the Phase 2 data will translate to this Phase 3 pivotal trial.  The company is taking a big swing looking to hit a home run by showing superiority, most likely to potentially justify charging a price in line with other rare disease treatments, at the risk of complete whiff.

VTX-801

France-based Vivet Therapeutics is another company developing a potential therapy for Wilson Disease. In March of 2019 Pfizer acquired a 15% stake in the company for €45 million along with an option to acquire the remaining 85% of Vivet for up to €560 million subject to certain data milestones from the Phase 1/2 trial of VTX-801 being met.

VTX-801 is an AAV-based gene therapy utilizing Anc80 serotype to deliver a gene coding for company’s proprietary miniATP7B copper transporter, a truncated version of the wild-type gene designed to fit within the carrying capacity of the virus. Vivet licensed the AAV-Anc80 vector from Massachusetts Eye and Ear, which is designed to increase gene expression in the liver and reduce immunogenicity compared to other AAV serotypes such as AAV8. That assertion has yet to be confirmed in the clinic though and in vitro work from the company suggests it may actually be more sensitive to neutralizing antibody titers than AAV8. Abstract 402 from ASCGT 2020 indicates that there are similar rates of individuals seronegative for Anc80 and AAV8 in the sample taken and concludes the following: “the high sensitivity of AAVAnc80 to NAbs was further confirmed in NHPs. Immunoadsorption was required for an efficient transduction of NHP liver, even in animals with low NAbs.”

Preclinical work published by Vivet demonstrates increased efficiency of transduction of AAV8-miniATP7B compared to AAV-ATP7B along with confirmation that the protein is functional with the ability to load copper to ceruloplasmin and transport excess copper for excretion.

Importantly, the authors note that their data indicate that for prevention of liver disease transduction of only 7-10% of hepatocytes would be needed while restoring ceruloplasmin levels to normal would require 17-23%. If this is demonstrated to be correct in humans the case for the feasibility of a functional cure with AAV gene therapy would be bolstered by what has been shown in the data from other liver directed treatments such as Ultragenyx’s DTX301 and DTX401. OTC Deficiency and GSD1a were predicted to require 3% and 10% of normal levels of the deficient protein respectively to demonstrate benefit and the therapies have shown promising efficacy data in their respective Phase 1/2 trials. 

While dosing has yet to commence in a clinical trial Pfizer highlighted this program at their investor day in September 2020, guiding for a BLA submission in 2025.  In November of 2020 Vivet and Pfizer received clearance to initiate GATEWAY, a Phase 1/2 study that was initially expected to enroll 16 participants commencing in early 2021. Per a recent update in May to the clinical trials posting the start for this study has been pushed back to August 2021 with an estimated primary completion in July 2023 so Pfizer’s 2025 BLA submissions estimate may prove to be optimistic. Vivet entered into a manufacturing agreement with Pfizer to provide the clinical supply for this study from their Chapel Hill, North Carolina facility that should help to minimize the potential risk of manufacturing related delays between Phase 1/2 and a pivotal Phase 3 trial.

In the GATEWAY trial safety and tolerability will be the primary endpoint with secondary endpoints including measurements of free serum copper, total serum copper, 24-hour urinary copper excretion and serum ceruloplasmin activity. Additionally, secondary endpoints will also include VTX-801 responder status, which is defined as ability to withdraw background therapy such as chelators or zinc salts at week 12 and maintain copper metabolism at 36. To monitor metabolism IV administration of a radioactive copper isotope, copper-64 (64Cu), is used, which allows for measurement of excretion as well as use of PET scan to how much 64Cu is retained in the liver. A recent presentation appears to suggest that this is the endpoint that the company will look to utilize as an outcome supportive of approval in a pivotal trial. Preclinical data in mice supporting efficacy on this endpoint was presented at EASL 2019, showing administration of 64Cu 3 months after a 5x10^12 vg/kg dose of VTX-801 resulted in a reduction in 64Cu retained in the liver compared to WD mice but appearing to fall short restoring the levels to those similar to seen in the wild type.

UX701

Ultragenyx acquired its Wilson disease program, UX701, through its $151 million acquisition of Dimension Therapeutics in 2017. Licensed from REGENXBIO and UPenn by Dimension, the company unveiled the program during its 2019 investor day. Similar to Vivet, Ultragenyx designed a novel truncated version of ATP7B called DelA ATP7B, which deletes non-essential metal binding domains to allow packaging for delivery using in AAV9 serotype. This transporter also demonstrated superior reductions in liver copper compared to wild type ATP7B:

Ultragenyx has disclosed preclinical data utilizing a 1x10^13 GC/kg and 1x10^11 GC/kg dose in “Toxic milk” Wilson disease mouse model demonstrating reductions in liver copper levels and increases in ceruloplasmin after four weeks that, similar to VTX-801, fall short of what is seen in wild type mice. It remains to be seen how this preclinical work will translate in humans and whether potential changes in these measures will continue to improve or even normalize over a longer period of time as ATP7B function is restored.

Ultragenyx received clearance in January of this year for their IND application for UX701 and plans to begin dosing patients in 2H 2021. The study will utilize a seamless Phase 1/2/3 design that will enable the company to proceed directly to a pivotal trial after a dose is selected in a Phase 1/2 rather than having to conduct an end of Phase 2 meeting with regulators to obtain alignment on a pivotal trial design. This should save the company about a year in the development timeline for this program and was enabled by this indication having a validated endpoint that the FDA will accept to support approval. The Stage 1 portion of the trial is expected to enroll 27 patients randomized 2:1 to UX701 at three escalating doses or placebo with a follow-up of 52 weeks. After that an optimal dose will be selected that will be used for stage 2, the pivotal portion of the trial. Stage 2 will enroll an additional 63 patients, again randomized 2:1 to UX701 or placebo.  The co-primary endpoints for this study will be copper regulation based on 24-hour urinary copper metabolism and percent reduction in standard of care therapy at Week 52.  In Stage 3 any patients who received placebo will be able to receive the Stage 2 dose and those who received UX701 in Stage 1 or 2 will continue to be monitored for long-term safety and durability of response.

The design of the withdrawal of standard of care endpoint is similar to what Ultragenyx has successfully utilized in its other clinical gene therapy trials for DTX301 and DTX401. In both of the Phase 1/2 trials for GSD1a and OTC Deficiency responding patients were weaned off of standard of care therapy with continued, durable effect from the therapy.  As with VTX-801, neutralizing antibodies are a concern and Ultragenyx will be screening for detectable pre-existing antibodies to the AAV9 capsid as part of the exclusion criteria for this trial. Estimates of neutralizing antibodies in the general population indicate that approximately 1/5th of the population may be ineligible for treatment with UX701. Based on commentary at an SVB Leernik conference earlier this year the company suggested that they expect to share some data from the Stage 1 portion that would not be anticipated to harm the integrity of the study after that stage is completed so depending on pace of enrollment investors can most likely expect an update in 2H 2022 or 1H 2023.

Outlook

Wilson disease appears to be an indication that is ideally suited for treatment with AAV gene therapy as a result of being monogenic, the liver being the target for delivery of the gene, and restoration of only a fraction of normal levels of the deficient protein being necessary. Estimates of the US and EU patient population range from ~10,000 (Alexion) to ~21,000 (Pfizer/Vivet) with Ultragenyx estimating ~50,000 patients in the developed world, making this a significant potential market that could support annual sales of $500 million to $1 billion.

While chelator prices were the subject of outrage recently due to well-publicized price hikes commercialization of gene therapy may face headwinds from the availability of generic treatments that generally work well and prevent this disease from being fatal. Based on commentary from Ultragenyx gene therapy may be able to differentiate from current standard of care by improving outcomes through normalizing of copper distribution outside the liver from restoring ceruloplasmin function. The company has suggested that some of the symptoms of Wilson disease may be more a result of inadequate distribution of copper as a result of non-functional ceruloplasmin rather than the excess copper. Additionally, in the case of Ultragenyx, improvements in manufacturing have allowed for a significant decrease in cost of goods that would support a lower price than what may be required for gene therapy programs in other indications to be viable. Using the company’s HeLA 2.0 platform at commercial scale of 2,000 liters the cost of making product for the upcoming clinical trial was 80% less than the cost for their DTX301 and DTX401 trials and that may be reduced even further if the company elects to transition UX701 to HeLA 3.0 in the future. While the last 50+ years have seen little innovation for Wilson disease patients the next few should bring into focus what a potential new standard of care could look like.

Disclosure:  The author is not a financial advisor and this article is not financial advice.  The author maintains a long position in RARE at the time of writing but reserves the right to sell at any time.