Roche restarts redesigned Phase 3 Huntington’s disease trial

Three months after announcing it would reduce dosing in its historic Phase 3 Huntington’s disease clinical trial – and pausing for a reset – pharma giant Roche announced on June 20 that it has reopened recruitment for the study, known as GENERATION HD1.

GENERATION HD1 aims to measure whether Roche’s gene-silencing drug, RG6042, will slow, halt, or perhaps even reverse HD symptoms. In late January, Roche announced that it had enrolled the first participant in the trial, which will include a total of 660 volunteers at more than 90 sites in at least 18 countries around the world.

In the original trial design, participants would undergo monthly spinal tap (lumbar puncture) procedures over 25 months. One third of participants would receive RG6042 each month and one third every other month. A third would get a placebo.

However, with new, promising data in hand from an open-label extension (OLE) of the Phase 1/2a trial, on March 21 Roche announced that it would decrease lumbar punctures to once every other month over the same period of time (click here to read more). In this revised design, one third of participants will receive RG6042 every other month and one third every four months. One third will receive a placebo every other month.

The change in dosing required Roche to stop the trial to obtain updated approval from regulatory agencies in the respective countries where the program is operating. Recruitment had to start from scratch, with all new volunteers. Roche completed the necessary details for resuming the trial in just a few months, as it had hoped.

“In March we announced our plan to amend the dosing frequency and study design, which will make study participation less demanding for patients, their families and HD centers,” Mai-Lise Nguyen, Roche’s HD patient partnership director, wrote to the HD community in a June 20 e-mail update on the trial. “Since then, our team has been working to implement study changes and obtain approvals from clinical trial review boards and authorities around the world. Today I am pleased to share that we have reopened the study for recruitment of new patients.”

Mai-Lise Nguyen (photo by Gene Veritas)

Initial authorizations received

With the lumbar punctures, GENERATION HD1 clinicians introduce RG6042 into the cerebrospinal fluid (CSF), which circulates along the spine and bathes the brain. The researchers hope that the drug will penetrate the brain sufficiently and, as a result, stop progression of HD. 

Lumbar punctures are routine and generally safe procedures, although they can sometimes cause side effects such as headaches and bleeding. In GENERATION HD1, the dosing will be a 20-minute outpatient procedure.

Roche changed the dosing based on new data taken from the OLE of the Phase 1/2a clinical trial of RG6042. Phase 1/2a was run by Ionis Pharmaceuticals, Inc., the original developer of the drug. Involving 46 volunteers in Canada, Germany, and the United Kingdom, that trial ended successfully in December 2017: the drug substantially lowered the amount of mutant huntingtin protein, the purported cause of the disease, in the patients’ CSF, which could be an indication of what’s happening in the brain – again, something to be studied in Phase 3.

All 46 participants took part in the 15-month OLE, which is run in support of the overall RG6042 research program. Nine months into the OLE, Roche had data indicating that it could reduce dosing in the larger Phase 3 study. Whereas 25 percent of the Phase 1/2a volunteers got a placebo, all 46 received the drug in the OLE.

“Initial clinical trial authorizations to start the amended GENERATION HD1 study have been received, and we expect to receive the remaining approvals soon,” Nguyen stated. “Recruitment timing will be different at each participating HD clinic/center, because the protocol amendment must be fully approved and in place at each study site before local recruitment may open. Our team is working to rapidly activate the updated study protocol at each site.”

An updated country list

Nguyen provided an updated list of countries currently hosting the GENERATION HD1 sites: Argentina, Australia, Austria, Canada, Chile, Denmark, France, Germany, Italy, Japan, The Netherlands, New Zealand, Poland, Russia, Spain, Switzerland, United Kingdom, and the United States.

Roche recommends that those interested in participating contact their local HD specialists. Individual site information will also be posted at ClinicalTrials.gov and ForPatients.Roche.com.

Individuals who had already started GENERATION HD1 before the announcement of the changes in dosing will be eligible to switch to GEN-EXTEND, an OLE study in which everybody receives RG6042 (no placebo).

Publication of the first data

The resumption of GENERATION HD1 comes in the wake of the first official publication of Phase 1/2a data. That article underscores the impressive results of the trial but also the need for careful study of RG6042 in Phase 3.

Co-authored by 22 scientists, including leaders of the Roche and Ionis HD teams, the article “Targeting Huntingtin Expression in Patients with Huntington’s Disease” appeared in the online edition of The New England Journal of Medicine (NEJM) on May 6 and in print on June 13.

The article confirmed that Phase 1/2a met its primary goal of demonstrating no serious adverse effects of RG6042.

The article also provided details demonstrating the extent to which RG6042 reduced the mutant protein in the CSF. However, it added that researchers still do not yet know whether that reduction in the CSF corresponds to a reduction in the human brain.

A ‘big leap forward,’ but with a critical need for Phase 3

The NEJM article also revealed that two tests showed results that could prove worrisome: temporary increases in the size of the ventricles (fluid-filled spaces) of the brain and in a biomarker (sign of disease) known as neurofilament light.

“Getting to the bottom of these potentially concerning lab tests requires a larger group of people, followed for a longer time,” commented HD researcher Jeff Carroll, Ph.D., in a May 7 HDBuzz.net article. 

In Huntington’s, the ventricles “appear to grow, as the [brain] tissue around them shrinks,” Dr. Carroll explained. This is “the opposite effect one would hope for if the drug was slowing brain shrinkage,” he added.

Regarding neurofilament light, Dr. Carroll observed that “this marker is released by sick and damaged brain cells called neurons, and researchers have previously demonstrated that it increases slowly and predictably in HD mutation carriers.”

The need to understand these test results is “exactly why Roche and Ionis are conducting a new, larger, study called the GENERATION-HD1 study,” Dr. Carroll continued.

Dr. Carroll concluded that “the now published results of the first study with a drug targeting the root cause of HD are a big leap forward for the community. They point towards refinements and cautions we should consider as we test the drug in larger groups of HD patients over a longer time.”

(Disclosure: I hold a symbolic amount of Ionis shares.)

Click on the links below for previous articles on RG6042.

"Roche: less frequent dosing for Phase 3 Huntington's clinical trial, easing burden on patients"

"Roche ramps up Huntington's disease clinical trial for early- to mid-stage patients, considers ways to expand research"

"Roche announces U.S., Canada sites for Phase 3 clinical trial for Huntington's disease drug"

"Roche announces first sites for key Huntington's disease observational study"

"Unpacking GENERATION HD1, the Roche Phase 3 Huntington's disease clinical trial"

"Roche Phase 3 clinical trial for Huntington's disease gene-silencing drug to enroll volunteers in early 2019" 

"New Ionis data show positive trends in clinical measures of Huntington's disease drug trial volunteers"

"Roche gears up for pivotal Phase 3 Huntington's disease gene-silencing clinical trial"

"The best news for the Huntington's disease community since the discovery of the gene: Ionis data revealed, Roche confirms jump to Phase 3"

"Ionis scientists provide initial assessment of successful Phase 1/2a Huntington's disease trial and discuss next steps"

"Ionis drug successfully reduces toxic Huntington's disease protein, paving way for Phase 2 trial of effect on patients"

Are pre-existing conditions returning, and Obamacare ending?

Nine years ago, with passage of the Patient Protection and Affordable Care Act (ACA) under Democratic President Barack Obama, I celebrated with an article titled “Good-bye, pre-existing conditions!”

Widely known as Obamacare, the ACA prohibited insurance companies from denying coverage to people with pre-existing conditions, a widespread practice that severely endangered the genetically unlucky. It also made health insurance available to millions of people previously unable to obtain it, and it extended family coverage for children up to age 26.

In 2012, the U.S. Supreme Court upheld Obamacare by a 5-4 decision, with conservative Chief Justice John G. Roberts Jr. joining the court’s four more liberal judges. However, with the long political fight over the ACA heating up again, and a more conservative Supreme Court, Obamacare could be abolished if the court agrees with right-wing challenges to it.

Along with many other disease groups, the Huntington’s disease community could face declining quality of care, increased costs, and renewed discrimination and stigma.

Hiding the central fact of my health

I am an HD gene carrier.

In my 2010 article on the ACA, I wrote that, because of the insurance restrictions for pre-existing conditions, I had “never used my health coverage to help me deal with the central fact of my health: my gene-positive test for this horrible brain disease.” I described the complicated and expensive lengths I went to in securing alternative assistance with HD.

Concealing my HD status from my health plan had produced “an absolutely absurd situation,” I observed in a 2019 HD Awareness Month podcast. People like me used to hide our conditions because we feared losing our coverage.

“Thank goodness for the Affordable Care Act,” I commented. The ACA “got rid of this nonsense about pre-existing conditions.”

Indeed, the enactment of the ACA had helped convince me to go fully public about my HD status in 2012 and inform my health plan of my HD status (click here to read more).

In all, this has made me a more effective HD advocate – and more organized and confident regarding my daily fight to stave off symptoms.

New attacks on the ACA

The Republican Party has officially opposed Obamacare, but – because of its popularity – failed to repeal it even when the party controlled both houses of Congress under President Donald Trump in 2017 and 2018. (The 2017 major tax bill signed by Trump did eliminate, starting this year, the ACA penalty for not having insurance.)

However, the Trump administration has carried out a multi-front attack on the ACA. Among other things, it has promoted insurance plans that do not comply with the protection for pre-existing conditions, and it has allowed states to impose work requirements for Medicaid recipients. America’s number of uninsured had fallen to record lows by the end of the Obama administration in early 2017, but the number has started to rise again.

Then, on March 25, Trump’s Department of Justice filed a brief supporting a Texas federal judge’s December 2018 ruling that the entire ACA was unconstitutional.

On May 22, California Attorney General Xavier Becerra, a Democrat and one of the lead defenders of the ACA, joined 20 other attorneys general in filing a brief in defense of the ACA in the U.S. Court of Appeals for the Fifth Circuit in New Orleans.

“The Trump Administration has made clear that it will not defend Americans’ healthcare and the law that tens of millions of Americans across the country depend on – so our fight continues,” Becerra stated in a press release.

The appeal will be heard on July 9. Depending on the ruling, the case could go to the Supreme Court. With two Trump appointees, the Supreme Court has become potentially more hostile to the ACA.

HDSA’s support

The Huntington’s Disease Society of America (HDSA) supports the ACA.

“HDSA believes that any attempts to repeal or dismantle the ACA without providing a replacement plan that maintains [the] protections and benefits for Americans impacted by complex and chronic diseases like HD is unacceptable,” the HDSA national office wrote me in a June 10 e-mail. “HDSA is committed to protecting access to healthcare for individuals impacted by HD.”

According to HDSA, the ACA “has created safeguards for vulnerable Americans who are impacted by chronic, complex diseases like HD from being denied healthcare coverage or being purposefully priced out of the healthcare market.” The ACA has “provided important avenues to access care for families with HD and we believe that they need to be protected.”

Thus, without the ACA or a robust equivalent, HD families could face greater difficulties in finding quality, affordable care.

We must not return to the ‘HD closet’

In addition to supporting HDSA and other advocacy organizations, HD family members can contact their state attorney general to support or join the appeal of the anti-ACA Texas ruling.

In California, where I reside, Becerra has sent several recent e-mails to political supporters asking them to sign a petition in support of the ACA. The e-mails have also asked for donations to help support the defense of the ACA.

According to Becerra, 133 million Americans have pre-existing conditions. He calls the ACA a “life-saving law.”

(The debate over the ACA has also helped stimulate calls by many of the 20-plus 2020 Democratic presidential contenders for a “Medicare for All” program. The debate is also related to the anti-science agenda of the Trump administration. I hope to address these issues in future articles.)

As I wrote in 2010, the passage of the ACA “brought a new beginning for the Huntington’s disease community – and for everybody in America.”

We must not regress to a system that forces people to hide in the "terrible and lonely HD closet," as so many of us did in the past.