2023-07-17 13:47:20 ET
Summary
- AMT-130, a gene therapy designed to inhibit the production of mutant huntingtin protein, has shown perplexing results in trials.
- The safety profile of AMT-130 is acceptable and further data is expected in Q4.
- Despite the confusing data, there are signs that patients may be benefiting from AMT-130.
Summary
AMT-130 is a AAV5 gene therapy designed to silence the huntingtin gene and inhibit the production of mutant huntingtin protein while also targeting the Exon 1 fragment. uniQure ( QURE ) released one and two year data from the high-dose (10 treated and 6 control) and low-dose (6 treated and 4 control) cohorts. Biomarker data included mutant huntingtin (mHTT) levels in the cerebrospinal fluid, neurofilament light chain (NfL) and brain volume measures. Patients clinical progress was measured by standard testing used for Huntington’s disease patients including Total Motor Score ((TMS)), Total Functional Capacity scores ((TFC)) and the composite Unified Huntington’s Disease Rating Scale (cUHDRS). Results were difficult to interpret and did not show a clear efficacy signal. The safety profile was acceptable, and further data which is anticipated in Q4 may provide clarity. Given few competitive therapeutics in this indication, the solid financial position of the company and the additional early stage pipeline assets, uniQure is rated a hold.
mHTT levels
AMT-130 is administered into the brain and designed to reduce mHTT levels at the site of the disease in the brain. Levels in the brain can not safely be measured, but CSF levels can be measured. One factor to consider is that it is unknown whether levels of mHTT in the CSF correlate with levels at the presumed site of the disease (striatum) within the brain.
The mHTT CSF results were perplexing. The control group’s mHTT levels increased approximately 5%. The low-dose patients showed an 8.1% reduction, whereas the high-dose cohort showed an increase in mHTT of 39.7%. Obviously, an increase is the opposite of what was hoped for. For investors, it brings into question whether there is target engagement given the drug is designed to reduce mHTT.
Management claimed the assay has a 30% coefficient of variability and given this, results are difficult to interpret in a small sample of patients. While the assay may not be ideal, it is also possible that the results indicate the drug is not achieving the desired effect. The CSO openly acknowledged that the data was difficult to interpret.
It is also important to note that mHTT has a poor relationship with disease progression in HD patients. It simply may not be the right biomarker to use in HD. In addition, Roche’s (RHHBY) tominersen did achieve a reduction of mHTT in the CSF. However, studies failed to show a clear clinical benefit for patients. In fact, there were some signs of toxicity. Some patients given tominersen had worse outcomes on a standard composite measure (cUHDRS) used in clinical practice than patients who received a placebo. Based on the tominersen results, it is not clear that lowering mHTT in the CSF is a biomarker which can predict whether an HD therapeutic will show benefit in patients.
NfL Neurofilament Light Chain
NfL may be a useful biomarker of neurodegeneration in diseases such as HD. Potentially, it can provide a signal as to whether a drug is slowing disease progression.
Neurofilament light chain levels were anticipated to rise due to the trauma of the neurosurgical procedure (drilling into the skull and injecting the gene therapy). Later, if AMT-130 was effective, levels were expected to decline.
The low dose cohort showed a 12.9% reduction from baseline in NfL at the 24-month mark. The lower dose data appears promising on this measure. While it is far from definitive, this could be interpreted as a positive sign.
However, in the high-dose cohort, neurofilament light chain declined from the expected initial elevation but remained well above baseline at 12 months. Two patients who had 18 months follow up also remained above baseline by 27%. Two patients in the high dose cohort experienced suspected unexpected serious adverse reactions, which could explain some of the NfL elevation at the high dose.
Overall, NfL levels are below baseline in 4 of 5 low-dose patients at 24 months and in 4 of 8 patients in the high dose cohort at 12 months, which suggests there may be a positive treatment effect. In the high dose cohort, NfL was trending downward, and the trajectory should be monitored at the next data readout.
The regulatory path in HD is unclear, as there are no disease modifying treatments for HD. Management noted NfL has been used for an accelerated approval of tofersen . In this case, FDA demonstrated “regulatory flexibility” and approved tofersen because its effect on NfL was reasonably expected to predict clinical benefit. In my view, uniQure will need additional data showing a sustained and substantial NfL lowering as well as data showing clinical benefit to make a convincing argument to FDA and EU regulators.
Whole Brain Volume
The preservation of total brain volume would be a positive treatment outcome. However, there was no statistically significant difference between treated patients and controls.
Functional, Motor and Cognitive Data
In my view, functional, motor and cognitive data are more relevant than biomarker data in determining a clear efficacy signal. Ultimately, what matters is patients experience a benefit. Management noted that Change in Total Motor Score and change in Total Functional Capacity score are potential endpoints if a phase 3 is conducted. In addition, there is a composite scale which incorporates multiple tests, the Composite Unified Huntington’s Disease Rating Scale (cUHDRS). On these measures, AMT-130 looks more promising.
Because of the small number of patients enrolled in the control group, the natural history cohort may give a better understanding of how untreated patients progress. Given the serious nature of the disease and difficulties in enrolling a control cohort, an issue to follow is how regulators will view a well characterized natural history cohort data in a pivotal trial.
Safety Profile of AMT-130
AMT-130 had an acceptable safety profile. The most common adverse events in the treated patients appear to be related to the invasive surgical procedure. Of significance, there were two suspected unexpected serious adverse reactions (SUSARs) in the high-dose cohort, both of which resolved. The DSMB has reviewed these events and cleared the dosing of additional patients.
Financials
uniQure recently received a $100 m milestone payment from CSL and entered into a royalty agreement which provided them with $375 m . At the end of last quarter, they had $315 m bringing the cash on hand close to $800m. The company appears to have adequate funding for several years of operations.
Conclusions
HD has proven to be a poorly understood and very difficult disease for drug developers. Given the $550 m market cap and the substantial cash on hand, the shares appear to be trading based on very little optimism about AMT-130.
In my view, it is encouraging to see some signs patients are benefitting from AMT-130. It is also encouraging to see NfL levels trending well in the low dose AMT-130 cohort. It is also promising that we don't see the worsening of some patients that was observed in Roche’s tominersen trial.
While the data was difficult to interpret and this readout did not provide the clear signal a biotech investor seeks to de-risk an asset, the level of pessimism implied by the share price may not be entirely rational. Susan Perlman, MD, who is a clinician who treats Huntington’s patients at UCLA, told STAT News the mHTT data was “confusing” but that the clinical data were “promising.”
uniQure intends to present new clinical data in Q4 showing how these patients progressed over time. There will be 18 and 30 month follow-up data on the US patients and initial 12-month data on a low-dose cohort from the European study. By Q1, 2024, they intend to discuss the more mature data set with regulators. These conversations will likely include discussions of the pathway for AMT-130, potential study designs and endpoints which will be acceptable to regulators. Investors may also wish to follow whether the company explains what level of clinical difference may support an approval.
Significant clinical decline appears to occur during a 5-year time span (see graph below). The impact of AMT-130, if any, will likely become more apparent as additional time elapses. Surely, if there is benefit, it should start to become very apparent at the 4-5 year mark.
While additional data and longer follow up may help to clarify the situation, investors should continually assess whether management makes decisions based on an honest and realistic assessment of the data. Currently, in my view, the management team is making a well-reasoned choice to continue to advance AMT-130. While uniQure has a large pile of cash, embarking on a large, expensive phase 3 trial could result in them burning it all in a futile attempt. Going forward, it may be prudent to simply observe treated patients and confirm an efficacy signal before embarking on an expensive phase 3.
There are an estimated 80,000 HD cases in the US and Europe. Currently, physicians can treat some of the symptoms, but there is little else a physician can do for these patients other than monitor the inevitable progression of the disease. Huntington’s disease is debilitating and often fatal. It represents a true unmet medical need. Time will tell whether uniQure’s gene therapy can offer a promising treatment for patients suffering from this devastating neurodegenerative disease. For now, uniQure remains a high risk, high reward investment.
For further details see:
uniQure: The AMT-130 Readout