Science progresses, however slowly, by testing hypotheses. Biotech investors are familiar with this concept through clinical trials.
Clinical trials are how drug developers test hypotheses about the molecular drivers of disease. It often takes years and hundreds of millions of dollars to arrive at an answer. Even then, results aren't always perfectly clear. That's usually due to the complexity of biology and simplicity of hypotheses.
For example, Huntington's disease appears to be caused by mutations in the huntingtin gene (HTT). Scientists aren't entirely sure how the huntingtin protein functions inside the body, but mice die without it. Similarly, high levels of mutated huntingtin protein (mHTT) can be detected in spinal fluid in individuals with Huntington's disease.
That leads to an obvious hypothesis worth testing: Can reducing the amount of mHTT treat Huntington's disease or slow the progression of the fatal neurodegenerative disease? Biotech firm uniQure (QURE) may be the first to find out. Its findings have implications for the entire field.
A Well-Designed Study Suggests uniQure is On the Right Path
UniQure is developing a one-time gene therapy that reduces levels of huntingtin protein in the brain. The drug candidate, named AMT-130, is administered through a neurosurgical procedure to ensure delivery into the brain. Preliminary results from an ongoing Phase 1/2 clinical trial suggest the experimental therapy is succeeding at reducing mHTT.
A group of 10 patients with Huntington's disease received a low dose of AMT-130 (six patients) or underwent an identical neurosurgical procedure without receiving the drug candidate (four patients). Doctors measured mHTT levels by sampling spinal fluid before receiving treatment and every three months after. Only seven individuals had measurable levels of mHTT at the start of the study. One year after treatment:
- The four evaluable individuals who received AMT-130 experienced an average mHTT reduction of almost 54%.
- Surprisingly, the three individuals who received the sham procedure experienced an average mHTT reduction of almost 17%. They had mHTT increases at each three-month sampling until the 12-month mark.
- Importantly, a measure of nerve damage appeared to subside over time in individuals treated with AMT-130.
The first part of the study was conducted to determine general safety characteristics of AMT-130. A future part of the study will administer a 10 times higher dose to new patients. The company will report data as they become available, but has now enrolled three dozen individuals across the globe for multiple studies. All individuals will be observed for at least five years to determine if the experimental treatment has slowed progression of Huntington's disease.
It's important to point out that although AMT-130 appears to reduce mHTT levels based on a small number of patients, doctors aren't sure if that will be enough to treat Huntington's disease. For one thing, the neurodegenerative disease impacts the whole body, which means lowering levels of mutated protein in the brain might not be enough to provide an effective treatment. Additionally, the drug candidate reduces levels of both working huntingtin's protein and mutated huntingtin's protein. A more selective tool that only reduces mHTT may be required for an effective treatment option.
Will uniQure Prove or Disprove the mHTT Hypothesis?
Despite the biological complexity of Huntington's disease and potential limitations of AMT-130, uniQure appears to have the smoothest path forward for testing the mHTT hypothesis. Previous efforts across the industry pipeline have all failed. Similar to AMT-130, none were selective for only mHTT. However, none achieved anywhere near 54% reductions of the mutated protein. Additionally, some resulted in more worrisome levels of nerve damage than AMT-130.
The most advanced effort in the industry is a partnership between Ionis Pharmaceuticals (IONS) and Roche (RHHBY) . The pharma titan led development of a drug candidate called tominersen, based on an RNA tool, that reduced levels of total huntingtin protein. A Phase 3 study was halted in March 2021, although the biopharma in January 2022 decided to reapproach development in younger individuals with less disease burden. The same approach has been taken in Alzheimer's disease studies.
Another effort by Wave Life Sciences (WVE) failed in even earlier studies. The small-cap biotech decided to develop a more targeted, next-generation drug candidate for Huntington's disease. Other programs in the industry pipeline promise to offer more convenient treatment options, such as using intravenous administration instead of neurosurgery, but have yet to enter the clinic.
Of course, if uniQure finds the mHTT hypothesis is too simplistic or AMT-130 isn't selective enough, then none of these efforts are likely to succeed. Investors should remain grounded and wait for data readouts in the next 36 months, but AMT-130 is worth keeping an eye on as a bellwether for Huntington's disease treatment progress.
