Tuesday, June 27, 2017

Ionis Huntington’s disease drug a step closer to a critical Phase 2 study


Ionis Pharmaceuticals has made two positive announcements about the historic Phase 1 clinical trial of its gene-silencing drug for Huntington’s disease: trial enrollment is complete, and the company will extend the study for all patients who complete Phase 1.

These are key steps on a multi-year path to possible Phase 2 and 3 trials that, if successful, would bring the trial drug, IONIS-HTTRx, to market. Typically, all three phases of a clinical trial project take at least five years, although nobody can predict the actual course of a trial.

IONIS-HTTRx aims to alleviate HD symptoms by reducing production of the huntingtin protein in brain cells (click here to read more). Ionis launched the Phase 1 trial in September 2015. Three dozen patents are taking part in the trial, expected to be completed by the end of 2017, at sites in Canada, Germany, and England. This first phase aims not to assess success in combating HD but rather simply whether the drug is safe and tolerable.

It marks the first time HD patients are receiving a substance aimed to attack the genetic causes of the disease. It’s also the first time they’re getting a drug via spinal injection.

“The safety and tolerability profile of IONIS-HTTRx in the completed cohorts of the Phase 1/2a study supports its continued development,” a June 22 Ionis news release stated. “Patients who complete the Phase 1/2a study will be eligible to participate in an open-label extension (OLE) study that Ionis plans to initiate in the next several months.”

“Open label” means all participants take the drug, in contrast with a “double-blinded” clinical trial like the current Phase 1, where half the patients receive a placebo and neither patients nor doctors know who is receiving the actual drug.

This month’s news provided the strongest indication so far that Ionis and its partner Roche, a much larger multinational pharmaceutical firm with vast clinical trial experience, will take IONIS-HTTRx into a larger, critical Phase 2 study, as early as 2018, to measure efficacy.

“Upon completion and full analysis of this study, the next step for this program will be to conduct a study to investigate whether decreasing mutant huntingtin protein with IONIS-HTTRx can slow the progression of this terrible disease," Frank Bennett, Ph.D., the Ionis senior vice president of research, said in the release.

Ionis has repeatedly indicated that a Phase 2 study would include U.S. trial sites.


Frank Bennett, Ph.D. (photo by Kristina Bowyer, Ionis)

‘Cautiously optimistic news’

The double-blinded protocol of the Phase 1 HTTRx trial insures that bias and other external factors don’t affect the trial results.

As noted, in an OLE each participant receives the actual drug, and usually at the highest dose tried in Phase 1. An OLE allows researchers to gather more data, examine the drug’s effects over a longer period of time, and better prepare for an eventual Phase 2. Patients also potentially benefit by receiving the drug longer.

The HD research website HDBuzz, which is produced by clinicians and scientists, described the Ionis announcements as “cautiously optimistic news.”

“News that the trial is fully recruited and the final patients are going through the procedures is a strong suggestion that even at the highest doses, the drug’s safety looks good,” the HDBuzz report observed. “Despite exhaustive safety testing before going into patients, any drug can produce unwanted effects, so that’s really the best news we could be hoping to hear at this stage.”

Regarding the open-label extension, it added, “We don’t want to read too much into a brief announcement, but running an OLE isn’t cheap for a trial sponsor, so this announcement certainly gives us optimism about the whole HTTRx program.”

Signs of HD in the blood

A separate research study, with results published June 7, could help Ionis and Roche researchers evaluate the results of the Phase 1 trial and plan the potential Phase 2 trial.

In what was described as a “major advance in the field of Huntington's disease and neurodegeneration in general,” a team of researchers has identified a potential blood biomarker for HD.

Biomarkers indicate a disease mechanism or drug impact. They are common for many diseases, but the complexity and inaccessibility of the brain have made it extremely difficult for researchers to find them for neurological diseases.

HD scientists have most recently focused on obtaining biomarkers from the cerebral spinal fluid (CSF). However, obtaining CSF, which requires puncturing the spine, is far riskier than drawing blood, the technique used in the new biomarker research.

Led by Ed Wild, M.D., Ph.D., one of the administrators of the IONIS-HTTRx trial in England, the new biomarker study demonstrated that a brain protein known as neurofilament light chain (Nfl) appears in the blood of HD patients and presymptomatic gene carriers. (Click here and here to read more.)


Dr. Ed Wild (photo from EdWild.com)

A less invasive measurement

Dr. Bennett of Ionis previously described Nfl as a protein involved in the cytoskeleton, or internal “scaffold,” of neurons. HDBuzz likened it to “the ribs of an umbrella.”

Dr. Wild’s team discovered that, the more advanced the stage of HD, the greater the amount of Nfl in the blood.

“This suggests that a blood test might be able to provide consistent information about the brain, in place of an invasive spinal tap,” HDBuzz commented. “We hope [Nfl] will be added to the arsenal of resources that are helping us to monitor HD and to develop new therapies.”

Indeed, the IONIS-HTTRx researchers previously noted that Nfl is one potential biomarker in the Phase 1 trial.

Further research is underway to confirm the Wild team's results and to determine to what extent Nfl can be used as a biomarker.

Pope Francis, Ionis, and the hope for a cure

The Ionis announcements about the clinical trial came as the 32nd annual convention of the Huntington’s Disease Society of America got underway in Schaumberg, IL. In addition to the news release, Ionis issued a letter to the HD community.

“We can assure you our number one goal remains our commitment to advancing IONIS-HTTRx development, a drug that has the potential to transform the treatment of HD,” the letter stated.

The positive news also comes in the wake of HDdennomore, the historic audience of the Huntington’s disease community with Pope Francis in Rome on May 18.

Dr. Bennett made a substantial donation to HDdennomore. He and several Ionis officials attended the audience. Dr. Bennett and his wife Paula sat in the front row along with leading HD scientists and dignitaries. They were greeted by Francis.

In his address, the pope recognized the geneticists and scientists “present here, who, for some time, sparing no energy, have dedicated themselves to studying and researching a treatment for Huntington’s disease. Clearly, there is a great deal of expectation surrounding your work: resting on your efforts are the hopes of finding the way to a definitive cure for the disease, but also of improving the living conditions of these brothers and sisters, and of accompaniment, especially in the delicate phases of diagnosis, at the onset of the first symptoms.”

If it succeeds, IONIS-HTTRx could fulfill those hopes and show the way to curing other neurological diseases.


Frank Bennett (left), Paula Bennett, and Gene Veritas (aka Kenneth P. Serbin) in St. Peter’s Square just before the audience with Pope Francis, May 18, 2017 (photo by Bianca Serbin)

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

(Click on the links below for past coverage of the Ionis HD project.)










Tuesday, May 30, 2017

Join the Facebook Live event (soon!) on Pope Francis’s historic audience with Huntington’s disease families


I want to invite the Huntington’s disease community – and all potential new supporters of the cause – to participate in my Facebook Live interview about Pope Francis’s historic HD audience on Wednesday, May 31, at 11 a.m. Pacific Daylight Time.

Conducted by San Diego Union-Tribune reporter Bradley Fikes, the interview will take place at this link: j.mp/sdutface. Participants can send questions and comments.

The interview will discuss details of the papal audience, where Francis declared that HD should be “hidden no more.” It will also allow for reflection on the significance of the event for the HD movement. (Click here to watch highlights of the audience).

Building on #HDdennomore’s goal of increasing global awareness of HD and removing the shame associated with the disease, we in the HD community can use the interview to expand our base of supporters.

Please invite others beyond your regular circle of friends, relatives, and acquaintances to watch.


Gene Veritas (aka Kenneth P. Serbin) with Pope Francis, who is holding a picture of Gene's late mother Carol Serbin, a victim of HD, and her long-time caregiver, the late Paul Serbin (photo by L'Osservatore Romano)

Sunday, May 21, 2017

Francis made a day of ‘superlatives’ for the Huntington’s disease community, says event co-organizer

Pope Francis created a moment of “superlatives” for the Huntington’s disease community in his historic May 18 meeting with HD-afflicted families, international advocate Charles Sabine said a day later, citing record involvement in the cause, global awareness, and a “poignant” focus on HD’s tough challenges.

A former foreign correspondent for NBC News and presymptomatic carrier of the HD gene, Sabine helped organize HDdennomore, Pope Francis’s Special Audience with the Huntington’s Disease Community in Solidarity with South America” (click here for background on the event).

Sabine, as did prominent HD scientist and Italian senator-for-life Elena Cattaneo, read an introductory statement preceding Francis’s own speech.

“Your Holiness, today marks a new chapter in the history of humanity’s forgotten families,” Sabine told the pontiff as the audience and web viewers from around the planet listened. “Never before has a world leader recognized the suffering of Huntington’s patients and their carers.”

He described HD as the “harshest affliction known to mankind” and also the “most misunderstood, and until today, the most hidden.” Despite that, Huntington’s has never defeated the human spirit, Sabine asserted. Francis could now affirm that “it is not a sin” to have HD.

Thanking the pope on behalf of the HD community, Sabine praised Francis’s “wisdom” and “compassion, which has shone the light of your church on our disease, at last, so that it be hidden no more.”

In his own stirring speech, Francis elaborated on some of Sabine’s points and declared that HD disease should indeed be “hidden no more!”

Visiting the HD families

The day after, Sabine visited the several dozen HD family members from South America, a main focus of HDdennomore, at their lodgings, the Passionist fathers’ monastery. Located in the historic center of Rome just south of the Colosseum and with a large inner courtyard, the monastery provided the HD families with an idyllic setting for repose and meals. HDdennomore provided transportation to the Vatican and other sites during the week-long stay in Rome.


Charles Sabine (center, white shirt), flanked by HDdennomore co-organizers Ignacio Muñoz-Sanjuan, Ph.D., and Senator Elena Cattaneo, Ph.D., and surrounded by South American HD family members (photo by Gene Veritas, aka Kenneth P. Serbin)

The guests included the juvenile-HD-afflicted 15-year-old Brenda of Buenos Aires, Argentina, the pope’s hometown, and 13-year-old Anyervi, a member of an HD family from Venezuela’s Lake Maracaibo region, the site for decades of critical research in the search for the HD gene led by Nancy Wexler, Ph.D., who attended the event. Both Anyervi and Brenda have been ostracized by other children because of prejudice regarding HD.

Before the pope’s arrival for the audience, Sabine called the two on stage individually. Anyervi received a soccer ball and jersey signed by Brazilian soccer superstar Neymar, who greeted the boy in a short video. Brenda was serenaded in person by Argentine smash-hit singer-songwriter Axel.

Sabine’s reflections

At the monastery, an upbeat Sabine circulated among the families and HD advocates, conversing and joking. He took a break to speak with me about his impressions of the event in its immediate aftermath.

GV: What is your feeling about the meeting with the pope?

CS: It’s mostly a feeling of immense relief that, after a year and a half of planning, on a day when a more than a million things could have gone wrong, nothing major did. That’s my immediate sense.

But I’m so extraordinarily pleased at the words of Pope Francis. That was beyond my control other than the set of notes which I gave him in preparation, which he requested, about the disease. He could not have been more eloquent, poignant, and to the point and focused on the real problems and issues that you and I and everyone else faces with this disease.

And he eloquently and, I believe, truthfully and sincerely made the point that this disease should be – and he used these words – “hidden no more.” And that is something that I could never really have dreamt would happen in my lifetime.

GV: That he’d actually use those words?

CS: Yes. But he did say – and this is important – that it is a great slogan but that it must become more than just a slogan. That’s now what we’ve got to do.

GV: So that’s the question, Charles: what comes next for “HDdennmore” and this whole movement?

CS: Well, I was a little surprised when I read in The Washington Post this morning that the “HDdennomore” event in the Vatican yesterday was the beginning of an initiative. That sounds a little bit daunting. It was the initiative to me! To hear it described as a beginning is both daunting and exciting. Okay, I’ll take that. Let’s call this just the beginning. Where next? Washington? London? We’ll see.

GV: So you’re kind of basking in the joy of this for the time being?

CS: Yeah, I’m just so pleased for all of these families who are standing here in this courtyard of this peaceful Passionisti convent here in Rome with all of these patients. I saw many of these patients a month ago in their homes in Maracaibo. Physically they appear better. They are absolutely flying. They are all smiling, they’re all laughing, they’re all talking.

Okay, they have just had a pretty amazing experience, but it just shows really what can happen. Already we’ve had messages from all over the world of people not only just congratulating us. I’m stunned how many people watched the event. I had no idea that so many people would watch it. I’ve had messages from people who were watching it in the middle of the night on the West Coast. There was one nurse whose family were watching it in the Philippines. People were watching this all over the world.


South American HD families preparing for a group photo at the Passionist fathers' monastery, May 19, 2017 (photo by Gene Veritas)

The reaction has already been intense. We’ve had messages of just not support for the event, but also financial bequests. Anyervi, the little 13-year-old who got the Neymar shirt, he’s already had a wealthy benefactor in Italy who’s asked to sponsor him now for the rest of his life. We’ve had other requests to help.

We had a meeting just yesterday, which followed after our event, with industrialists who are looking into ways in which they can help South American families, in particular in Venezuela, where one of them has land he’s donating now with a view to providing food. There was a clinicians’ meeting after that. They were coming up with ideas for working together to get drugs and medical services into South America. It’s already happening.


Anyervi of Venezuela (photo by Gene Veritas)

GV: Did you have a meeting with a cardinal and/or other people in the Vatican afterwards?

CS: Yes, I wasn’t present at them, but there have also been meetings with cardinals to get across the points that Pope Francis made so eloquently and directly about how this disease has been ignored.

And he admitted it. He was very frank. The pope said and was implicitly admitting that his church had failed. He didn’t want to say it like that, but he said these people have been ignored. He didn’t say these people have been ignored, but not by the Church. He said they’ve been ignored. That means they’ve been ignored by the Church. And that’s a wonderful admission.

What we need to do now is to insure that his words are now made into actions on the ground by the cardinals, the archbishops, and the priests across not just South America but all around the world to make it understood that this should be a disease that no one should feel, as I said in my words there, that it is a sin. I spoke to the pope yesterday. I said thank you for making clear the truth – one of the truths that’s been omitted from this disease for centuries – which is that it’s not a sin to have Huntington’s disease in your family.

GV: The pope mentioned the issue of embryonic stem cells. Do you want to comment on that?

CS: It was a little bit of a shame that he did that. It’s the one thing about that speech that was a little bit disappointing. I don’t think he needed to get into that because it wasn’t particularly relevant to that event.

Unfortunately, many of the newspapers from around the world have taken that as a headline, which is a bit of a shame. [The Pope stated that no scientific research, no matter how “noble” its goal, “can justify the destruction of human embryos.”] Of course, that’s an issue that’s still a stumbling block with the Catholic Church. But I personally don’t think that for one second his mentioning that in his talk should take one iota away from the fact that it was a resounding, total success.


Pope Francis during the HDdennomore special audience (photo by Gene Veritas)

GV: Do we know who wrote the pope’s speech?

CS: I don’t know. I gave him three pages of notes that talked about what we go through, including, in particular, the shame and the stigma. And certainly the themes that were in that I saw in there. I don’t whether he wrote it or if he had others. But they wrote it very, very well.

It was really, I thought, brilliantly working in, as he would naturally, the point of mercy and Jesus. The event yesterday personified yesterday more than any other event exactly that new philosophy of his of putting mercy before doctrine, which is not a popular one amongst many on the right.

But the fact is, there were so many superlatives yesterday. There were 1,700 people there, according to the Associated Press and Reuters. That was by far and away the largest collection of people with regard to Huntington’s disease, by some measure. There were 150 patients – at least – that were there, and probably a lot more. That in itself is another record. There have never been that many people in one room affected by Huntington’s disease. There could have been people in there affected by disease that we didn’t meet.

There were at least 27 countries represented. I don’t know whether that’s a record, but certainly the other two are.

(My trip to Rome was made possible by the College of Arts and Sciences, the Frances G. Harpst Center for Catholic Thought and Culture, the International Center, and the Department of History of the University of San Diego. I am grateful for the institutional and moral support of my colleagues and students.)

Friday, May 19, 2017

Pope Francis declares: Huntington’s disease should be ‘hidden no more’

Wow! In a stirring speech at the Vatican transmitted globally, Pope Francis declared to the world on May 18 that Huntington’s disease should be “hidden no more!”

“It is not simply a slogan, so much as a commitment that we all must foster,” the head of the Catholic Church said of the idea embraced by the roughly 1,500 HD family members and supporters gathered at the Paul VI Audience Hall just a few yards from St. Peter’s Square. They had gathered for "HDdennomore: Pope Francis's Special Audience with the Huntington's Disease Community in Solidarity with South America."

“The strength and conviction with which we pronounce these words derive precisely from what Jesus himself taught us,” the pope continued in Italian, as Spanish and English speakers listened to a simultaneous translation on headsets. “Throughout his ministry, he met many sick people; he took on their suffering; he tore down the walls of stigma and of marginalization that prevented so many of them from feeling respected and loved.”

Click here to read the full text of the speech in English.

After the speech, the highly popular and charismatic Pope Francis stopped to greet, hug, kiss, console, and have selfies taken with about 300 HD family members, HD researchers, pharmaceutical company representatives, and dignitaries seated in the front rows of the auditorium.

Overtaken with the pope’s powerful presence, some people cried uncontrollably as he stood before them.

The emotional charge traveled across the crowd. I welled up with tears as he got closer to my family and me in the third row.

After greeting my wife Regina and daughter Bianca and putting his hands on the head of my 78-year-old mother-in-law Lourdes, Pope Francis arrived at my place.

As I had planned, I showed the pope a picture of my mother Carol Serbin and father Paul Serbin, well-dressed and smiling in a formal pose, a photo taken after she had already been diagnosed with HD.

“My mother died of Huntington’s,” I told the Pope in his native tongue of Spanish. “My father cared for her for twenty years.”

I gave Francis a copy of each of my main books on the history of the Church in Brazil, explaining the theme of each with a brief phrase: priestly training and the Church’s struggle against the dictatorship in Brazil. I knew the themes were dear to him as the leader of the world’s Catholic clergy, respected colleague of Brazilian Catholic leaders and their flocks, and untiring proponent of social justice.

Francis said nothing, but he looked me in the eyes.

Somehow, my hands were now firmly holding the pope’s, and I told him: “Many thanks for supporting our community!”






Gene Veritas (aka Kenneth P. Serbin) with Pope Francis, May 18, 2017. In foreground, with back to camera, Bianca Serbin (photos by Regina Serbin).

Then Francis moved on to the next person.

When he finished circulating among the people, Francis returned to the stage, looked back at us and waved, and then exited with his papal entourage.

After listening to some closing music by performers from HD families, we filed out of the auditorium.

As I wrote in a blog note my cell phone, I felt “drunk with excitement” as I left with my family, hugging and taking a selfie with event co-organizer and HD global advocate Charles Sabine, greeting fellow advocates from South America, and at one point becoming disoriented and nearly tumbling to the ground. Regina became concerned that I would injure myself.

We had done it! We had witnessed Pope Francis decisively place Huntington’s disease on the world agenda.


Above, the audience at the May 18, 2017, papal audience on Huntington's disease. Below, Gene Veritas and Charles Sabine (photos by Gene Veritas).



(Click here to watch the audience on the Vatican’s YouTube channel. In my next article I will comment further on Francis’s HD speech and explore in detail the event and its impact.)

(My trip to Rome was made possible by the College of Arts and Sciences, the Frances G. Harpst Center for Catholic Thought and Culture, the International Center, and the Department of History of the University of San Diego. I am grateful for the institutional and moral support of my colleagues and students.)