A key Huntington’s disease trial remedy gets Orphan Drug Designation, as yet another young life is cut short

Ionis Pharmaceuticals, Inc. (formerly Isis Pharmaceuticals) has achieved another milestone in its search for a treatment for Huntington’s disease: on January 5 the company announced that the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation for its gene-silencing drug, currently under study in a clinical trial in Europe and Canada.

The FDA designation, intended to facilitate development of the test drug IONIS-HTT_Rx  by offering financial incentives and assistance, could not come at a better time. Huntington’s disease patients – like 18-year-old Terry Leach of San Diego, who died the morning of January 2 – continue to succumb to this devastating, untreatable disorder.

“Although the toxic protein produced from the huntingtin (HTT) gene in HD patients has been a target of interest for many years, IONIS-HTT_Rx is the first therapy to enter clinical development that is designed to treat the underlying cause of this fatal disease,” Frank Bennett, Ph.D., Ionis’s senior vice president of research, said in a company press release. “The granting of Orphan Drug Designation in both the U.S. and Europe highlights the significant need for a drug that could transform the treatment of HD.”

HD-affected Phase I clinical trial volunteers in London received the first dosing of IONIS-HTT_Rx in the October 2015 (click here to read more). IONIS-HTTRx could potentially reduce, partly reverse, and even prevent symptoms.

Likely ending in 2017, Phase I is testing primarily for safety and tolerability. If it is successful, Phase II and III trials measuring the drug efficacy’s would ensue. Together the three phases of a trial typically take at least five years. If the trial is successful, a drug could become available around 2020.

Frank Bennett, Ph.D. (photo by Dr. Ed Wild)

Increased dialogue, helpful benefits

“We were pretty excited to get Orphan Drug Designation,” Kristina Bowyer, Ionis’s executive director of patient advocacy, said in a phone interview on January 5. Ionis is based in Carlsbad, CA.

The designation means that the FDA recognizes “the severity of the disease and the limited population,” she noted.

The designation creates an opportunity for increased dialogue between Ionis and the FDA regarding the IONIS-HTT_Rx clinical trial, Bowyer explained.

Such extra communication can help resolve the unique issues of orphan disease trials. Because an orphan disease like HD involves fewer than 200,000 patients and very specific approaches to treatments, the design of clinical trials is atypical, Bowyer said. The smaller number of potential volunteers also means that the FDA might have to approve a smaller than normal trial, and sometimes perhaps even a faster trial, she added.

“It’s an area where our technology is well-suited,” Bowyer continued, referring to the antisense oligonucleotides that form the backbone of all Ionis drugs. “We have been able to focus on several rare diseases with a known target.”

By law, as outlined in the press release and in an e-mail from Bowyer, the Orphan Drug Designation includes significant financial benefits for Ionis: seven years of market exclusivity in the U.S. if the FDA approves the drug, tax credits related to clinical trial expenses, FDA assistance in clinical trial design, and a waiver of Prescription Drug User Fee Act filing fees – over $1 million per drug as of fiscal year 2009.

“These benefits help manufacturers recover the costs of developing a drug for small numbers of people,” Bowyer wrote. The Orphan Drug Act was signed into law in 1983.

Kristina Bowyer (photo by Gene Veritas)

Trial ‘moving along well’

In IONIS-HTT_Rx, HTT stands for the gene huntingtin, and Rx for medical treatment. The train has just recently begun, so, Ionis has reported no official update at this time.

“Everything is moving along very well,” Bowyer said.

The new name

Ionis has also adapted well to its name change, announced on December 18, 2015, in response to concerns about confusing the name Isis Pharmaceuticals, Inc., with the acronym “ISIS” used in the English-language media for the Middle Eastern terrorist organization, the Islamic State. Isis Pharmaceuticals was founded in 1989.

“We want people when they hear or say our name to think about the incredible drugs we’re developing and not a terrorist group,” Wade Walke, Ph.D., vice president of communications and investor relations, told the press.

Ionis chose its new name based on employee suggestions.

“It seemed to me that everybody came together and decided that Ionis was a nice-sounding, feeling name, as soon as someone hit on it,” said Stanley Crooke, M.D., Ph.D., Ionis’s chairman of the board and CEO. The new moniker is a so-called empty vessel name and has no inherent meaning other than what the company does, he added.

Said Dr. Crooke: “We’re here for the patients. We’re not here for our name.”

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

The Ionis logo

Too late for Terry, other ‘HD angels’

I remember that Dr. Crooke spoke the same phrase – “We’re here for the patients” – when I met him briefly during one of my first visits to the company in the late 2000s.

I also remember visiting Terry Leach on Labor Day 2015. He was slowly but inexorably slipping away from the ravages of juvenile HD, a particularly devastating form of the disease (click here to read more about my visit).

Nevertheless, I was still shocked by his death on January 2.

What a horrible time to lose a family member. New Year’s will forever remind Terry’s mother Angela and his siblings of his passing.

My immediate reaction that morning was one of intense anger.

No 18-year-old should die!

Having had the privilege of knowing Terry and his family, I felt that I had failed as an advocate to speed the progress towards treatments.

Why hadn’t the Ionis trial come in time to save Terry and the other “Huntington’s disease angels” who have passed in recent weeks?

I know that HD researchers may have similar thoughts, as they work with the specter of this killer disease ever looming.

Terry Leach (family photo)

Keeping the faith

Later in the day, knowing that I needed to transcend my anger and sadness, I recalled that a new year always brings hope. As I took a long, strenuous walk with my dog through our hilly neighborhood, I renewed my resolve to fight HD in 2016.

I spoke to Angela a few times that weekend. Instead of a wake and church service, the family will hold a remembrance for Terry at the family home on January 16. A Christian minister will preside.

At Angela’s request, I wrote some words for the back of the remembrance cards she’s having made: “With his infectious smile and fortitude, Terry set an example for all to follow. His life was short, but full of love and joy. He is now free to walk with the Lord.”

Understandably, Angela was too drained to talk much. She did confirm that Terry – despite his inability to talk, his confinement to a wheelchair, and years of ingesting food through a feeding tube – had achieved his high school diploma. He had attended school through mid-2015, receiving assistance in a program for the disabled.

I asked Angela if she had any words for the HD community.

She said: “Just to keep their faith.”

Angela Leach in 2012 holding artist Lee Ellingson's drawing of her son Terry as "SuperTerry," the superhero who knocks out Huntington's disease (photo by Gene Veritas)

Might I finally take part in a Huntington’s disease clinical trial? An update on the latest research

In the 20 years of my family’s fight against Huntington’s disease – we discovered my mom had HD the day after Christmas of 1995 – I felt this past week for the first time that I might have a chance to avoid its inevitable, mind-destroying symptoms.

On October 26, I learned about a new clinical trial aimed at rescuing brain cells from the degeneration caused by Huntington’s.

Called “SIGNAL” (alternatively, VX15/2503 Treatment for Huntington’s Disease), the trial will include asymptomatic carriers of the HD gene like me who are close to predicted age of onset. Made by the Rochester, NY-based biotech company Vaccinex, VX15/2503 is a monoclonal antibody, a type of molecule essential in molecular biological research.

Monoclonal antibodies are used in various forms by companies such as Vaccinex to treat an increasing number of conditions such as cancer. Vaccinex is also enrolling volunteers in a VX15/2503 trial for multiple sclerosis. Vaccinex believes the very same compound might help alleviate a host of other neurodegenerative diseases.

“The thought is that if we could give this drug early enough we can actually slow the progression of Huntington’s, and that’s really exciting,” said Jody Corey-Bloom, M.D., Ph.D., the director of the Huntington’s Disease Society of America Center of Excellence for Family Services and Research at the University of California, San Diego. She spoke to more than 50 people attending her annual HD research update presentation at the San Diego support group on October 26.

Jody Corey-Bloom, M.D., Ph.D. (photo by Gene Veritas)

Aiming to halt progression, delay onset

Dr. Corey-Bloom, who's provided research updates to the support group since 2005, kicked off this year’s presentation with a review of the historic news on October 19 that HD patients in England had received the first dosing of an Isis Pharmaceuticals drug, ISIS-HTT_Rx, aimed at stopping the disease at its genetic roots. ISIS-HTT_Rx is an antisense oligonucleotide (ASO), an artificial strand of DNA (click here to read more).

SIGNAL, initiated in June, is the “biggest” news on the HD clinical trial field scene since the development of ASOs for use in HD, Dr. Corey-Bloom said. SIGNAL marks the first ever use of a monoclonal antibody in an HD clinical trial, she noted.

“So we’re not just treating motor signs,” she said of SIGNAL. “We’re actually trying to slow the progression. And the reason is that this also belongs to a class of drugs that blocks inflammation in the brain in animal models. And so the hope is that we could either delay the onset or slow the progression.”

VX15/2503 would help HD patients by reducing inflammation in the brain. Scientists primarily from the lab of world-renowned HD expert Michael Hayden, M.D., Ph.D., in collaboration with Vaccinex researchers, published a breakthrough study in April in the journal Neurobiology of Disease demonstrating how the use of a monoclonal antibody restored health in HD mice.

Vaccinex is one of a growing number of biotech and pharmaceutical companies that have delved into the search for HD treatments as research has greatly expanded.

As the scientist-written HD research site HDBuzz noted last February, other investigators are seeking ways to use other antibodies in the quest for treatments.

You can watch Dr. Corey-Bloom’s research update, which includes details on numerous other hopeful projects, in the video below.

Update on Huntington's Disease Research 2015: A Presentation by Dr. Jody Corey-Bloom from Gene Veritas on Vimeo.

Including presymptomatic volunteers

HD clinical trials have rarely included presymptomatic people because of ethical concerns and the inability of science to measure a meaningful effect.

However, SIGNAL includes presymptomatic individuals for several reasons, in part because ways of detecting and interpreting the symptoms have become ever more effective, Dr. Corey-Bloom explained.

“You have to be gene-positive, but you don’t even have to have a diagnosis, because they believe that the drug itself is not going to hurt you,” she said, adding that the current stage of the SIGNAL trial (Phase II) is primarily to confirm its safety. (Later a Phase III would test the drug’s efficacy.)

SIGNAL will evaluate changes in participants’ brains using “very unique, very high-level, high-quality imaging,” she said. “They’re doing very special PET studies, and they’re also doing very special MRI studies, DTI, diffusion tensor imaging, and so just a lot of very, very special techniques that are being orchestrated by the Massachusetts General Hospital and [researcher] Diana Rosas.”

Measuring the effects

One attendee asked specifically how a presymptomatic individual would know whether onset had been delayed.

“I think the imaging data is going to be really compelling,” Dr. Corey-Bloom said, noting that previous research has abundantly demonstrated changes in the brain a decade or more before onset, as well as precise measurements in those changes over time. “I think they’re going to be able to tell that it isn’t declining the way people who aren’t being treated is declining.[…] If you’re in the early stages and stay there, that would be pretty impressive, too.”

Involving 36 volunteers at 13 sites across the country, SIGNAL will deliver VX15/2503 intravenously once per month over twelve months in one group and over 18 months in a second group. Dr. Corey-Bloom, whose Center of Excellence enrolled the first patient in SIGNA, said that each infusion would last about an hour. (Click here for the official details of the trial, which will be administered by the Huntington Study Group [HSG]). The HSG just completed its 2015 meeting, held October 21-24 in Tampa, FL.

Further information about SIGNAL in the San Diego region is available at 858-246-1254.

Confidence, but….

I will call that number very soon to learn more about my eligibility and the risks involved.

I tested positive for HD in 1999, and my mother died of the disorder in 2006 at the age of 68 after a two-decade battle. I’m almost 56, a stage where my mother already had involuntary movements and suffered from cognitive loss.

After attending the HD support group and seeing symptomatic friends, I’m always worried about onset.

Dr. Corey-Bloom’s recap of the good news about the long-awaited Isis clinical trial left  me with a feeling of confidence that someday we will defeat HD – but perhaps not in time to stop my onset. The Isis trial does not include presymptomatic individuals, and, even if successful, it could take five, ten, perhaps even 20 years for the approach to have a significant impact on the disease.

Wishing for a ‘normal’ life

However, after hearing about SIGNAL for the first time, a flood of new emotions began to pour over me.

I immediately felt hope for my friend Sharon Shaffer, my HD sister, and other HD-affected individuals in the audience.

Sharon Shaffer and mother Fran Walker (photo by Gene Veritas)

I awoke at 3:45 the next morning full of energy. Unable to sleep again, I worked on processing the video of Dr. Corey-Bloom’s talk.

“My 20th year attending support group – what a difference!” I wrote in my notes. “Treatments and trials, people asking questions about real scenarios, not just long-off hypotheses. PLUS: I learned of a trial that I can maybe take part in and see symptoms prevented. What if my career can be ‘normal’ and my life ‘normal’?”

I’ve hardly ever had such positive thoughts, although I recognize that I am extremely lucky to have remained asymptomatic this long.

Risks vs. benefits

My wife, who has seen so many of her own plans dashed because of HD, was pleased to hear about SIGNAL.

She hopes every day for a treatment to save me, as well as others, from the devastation she witnessed in my mother.

As I gather more information in the coming weeks, and if I am eligible to participate in SIGNAL, I will weigh risks and benefits with her, my physicians, and members of the HD community.

My immediate concerns: could VX15/2503 cause harmful side effects or even trigger HD? Would participation somehow prevent me from taking part in other trials in the future?

‘Unimaginable scenarios’

Regardless of my participation, I will follow this project with keen interest – as surely will the rest of the HD community.

As with the Isis compound, there is no guarantee VX15/2503 will work.

However, it is yet another shot on goal in the search for effective treatments. The more shots, the better the chance of success.

The HD community can now envision scenarios unimaginable 20 years ago. That's significant progress.

Huntington’s disease patients get first dosing in historic Isis Pharmaceuticals’ gene-silencing drug trial

Huntington’s disease patients in England have received the first dosing of an Isis Pharmaceuticals drug, ISIS-HTT_Rx, aimed at stopping the disease at its genetic roots.

The patients displayed no immediate complications. This so far confirms expectations that the gene-silencing drug would be safe to use, although clinical trial administrators will continue to make critical observations in the coming months. Other dosings will occur. The drug’s efficacy will not be analyzed until later stages of the trial.

An announcement came October 19 that a small number of Phase I clinical trial participants at University College London (UCL), the lead site for study, had received injections via spinal cord of the Isis compound, according to a UCL news release.

“It's the beginning of quite an important journey in Huntington's disease,” Sarah Tabrizi, Ph.D., the director of UCL’s Huntington's Disease Centre and the global chief clinical investigator for the trial, told the BBC. “It is clearly very early but this is a step forward.

“The preclinical work shows that if you lower production of the mutant protein then animals recover a large amount of motor function. Huntington's is a really terrible disease that blights families. I know a mother whose husband and three children were affected. This would have a massive impact [if it works].”

Sarah Tabrizi, Ph.D. (photo from University College London website)

Slowing or preventing the disease

The news comes just three months after Isis announced the official start of the trial, the first time HD patients are receiving a substance aimed to attack the genetic causes of the disease. Isis has partnered with the Swiss-based pharmaceutical giant Roche to facilitate the clinical trial and, if it’s successful, the marketing of the drug.

Isis officials were unavailable for comment on October 19 but the main scientist spearheading the development of ISIS-HTT_Rx, which signifies a medication for HD, commented in the UCL release.

“We designed ISIS-HTT_Rx to target the huntingtin gene and reduce the production of huntingtin protein, which is the known cause of the disease,” stated Frank Bennett, Ph.D., the Isis senior vice president for research. “This approach has the potential to prevent or slow the progression of this disease. If this first-in-human trial proves the drug is safe, we look forward to continuing our successful partnership with Roche to bring the drug to market.”

Dr. Bennett has previously described the drug, scientifically known as an antisense oligonucleotide (oligo), as a “laser-guided missile” targeting a “specific messenger RNA that causes a particular disease and kill it or take it out of the body so that you don’t produce that messenger RNA.”

Isis announced the details of the trial in August 2014 (click here to read more).

Frank Bennett, Ph.D., senior vice president for research at Isis Pharmaceuticals (photo by Dr. Ed Wild)

Safety and tolerability first

The Phase I trial involves patients at UCL and also at various sites in Canada and Germany. Across all sites, a total of about 36 patients will take part. Phase I trials focus primarily on the safety and tolerability of a drug. The study will also help determine the frequency and size of dosages for eventual Phase II and Phase III trials, which measure efficacy.

All of the volunteers have early stage HD. Because of the use of spinal taps to administer the drug and the highly experimental nature of the oligos, no non-HD-affected individuals are taking part as controls.

No announcements have yet been made about dosing of patients in Canada and Germany.

According to the UCL release, the ISIS-HTT_Rx is taking place in the new Leonard Wolfson Experimental Neurology Centre, a custom-built facility designed to accelerate innovative treatments for neurodegenerative diseases.

“The administration of the first doses of ISIS-HTT_Rx marks the Centre's first use as a phase 1 'first into human' trial facility, as well as the first time that an experimental drug has been given by spinal injection in the 156-year history of the National Hospital for Neurology and Neurosurgery, part of University College London Hospitals (UCLH) NHS Foundation Trust,” the release stated.

What’s next?

“The first volunteers have been treated without any immediate complications,” the scientist-written HD research site HDBuzz observed. “The next year or so will be a period of intense study of these trial volunteers to make sure that they don’t have unexpected complications from the treatment. They’ll also be examined for a range of measures of whether or not the drug is working, which will provide critical information for planning future HD gene silencing studies.”

Depending on the pace of recruitment, Phase I most likely will end in 2017. If Phase I is successful, Phase II could follow no sooner than nine months later. All three phases of a clinical trial program typically take at least five years.

Historically, only ten percent of clinical trials ever result in a marketable drug.

Regardless, the HD community has crossed a significant threshold. Science has yet to produce an effective treatment for HD, as well as for Alzheimer’s, Parkinson’s, and other neurological disorders. HD could be the first.

Hope is palpable.

As a carrier of the deadly HD gene who lost his mother to the disease in 2006 and has tracked the Isis project since 2007, I am thrilled that our fellow HD community members have successfully made the first step in this historic clinical trial. They deserve our enthusiastic applause for volunteering.

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

Reinforcing the global fight against Huntington’s disease: a visit to Brazil and a reminder of our common struggles

The global cooperation necessary to defeat Huntington’s disease requires the bridging of cultural divides. It entails recognition of each country’s unique needs and contributions – but also of the common struggles involved.

With this in mind, last month I embarked on another phase of my own international advocacy by traveling to Brazil, the country I have studied since 1986, to deliver a speech on HD and build new connections for the cause.

The world’s fifth most populous country, with over 190 million people, Brazil occupies a significant place on the world’s HD map. Perhaps 19,000-plus Brazilians suffer from the disease, and tens of thousands are at risk.

Thus, once the global HD clinical trial and research study platform known as Enroll-HD gets under way in Brazil, the country’s potential contributions to the search for effective treatments will increase substantially (click here to read more).

A ‘bi-cultural’ perspective

As I have done almost every year over the past three decades, I visited Brazil primarily to work on my ongoing research in Brazilian history. In all, I have spent nearly seven years there. In 1991, during my Ph.D. research in Rio de Janeiro, I met my wife Regina.

Brazil is my second home. I refer to myself as “bi-cultural.”

Even before I joined the board of the San Diego chapter of the Huntington’s Disease Society of America in 1998, I established contact with Brazilian HD activists who founded the Associação Brasil Huntington (ABH) in 1997.

As a carrier of the HD genetic defect, I spoke in 2013 about my personal strategies for avoiding onset of symptoms at the sixth World Congress on Huntington’s Disease, held in Rio (click here and here to read more).

Gene Veritas (aka Kenneth Serbin) at Ipanema beach in Rio de Janeiro (photo by Regina Serbin)

Combating genetic discrimination

During this most recent trip, I advocated for HD-related issues in my meetings with political leaders.

In 2005, the Brazilian Senate passed a bill protecting citizens against genetic discrimination. However, the Câmara dos Deputados (the House of Representatives), has yet to take up the matter. Until then, the bill cannot become law.

Senator Aloysio Nunes Ferreira Filho, who ran for vice president in the 2014 election on the losing ticket of the opposition Brazilian Social Democracy Party, supports the legislation. During my visit to his office in Brasília, the capital, he phoned a colleague in the Câmara to urge action on the bill.

Senator Aloysio Nunes Ferreira Filho (above, photo by Gene Veritas) and Gene Veritas in the chamber of the Senado Federal in Brasília (below, photo by Lucas Souza) 

Defending the rights of the disabled

Later, in São Paulo, South America’s largest industrial and financial hub, I attended a presentation by the famous liberation theologian Leonardo Boff about the geopolitical state of the world, the threat to the global environment, and the current political crisis in Brazil.

The event was moderated by Paulo de Tarso Vannuchi, who served as Minister of the Special Secretariat for Human Rights from 2005-2011 in the government of the ruling Workers’ Party.

Vannuchi briefly introduced me to leaders of the National Council for the Rights of the Disabled. I committed to furnish them with information about HD and put them in touch with the ABH.

Vannuchi told the audience of 60, which included clergy and grassroots social activists, of my HD advocacy and suggested that the reporters present interview me.

Paulo Vannuchi, former Minister of the Special Secretariat for Human Rights (photo by Gene Veritas)

That same day I gave an interview to the TVT television outlet commenting on the importance of Boff’s speech. (You can see the report on the event, including my commentary, by clicking here).

Shortly after my return from Brazil on July 22, one of the reporters present at the event, São Paulo-based radio broadcaster Marilu Cabañas, interviewed me via phone about HD for her program. Shocked to hear of police detentions of HD-affected individuals in both Brazil and the U.S. because of ignorance about the disease, she headlined her report with that fact.

Bioethical challenges

I gave my speech, “Huntington’s Disease, Bioethics, and the Promise of Biotechnology,” on July 20 at the Universidade Candido Mendes (UCAM) in downtown Rio de Janeiro.

I have known the rector, Candido Mendes, for more than 20 years. My friends and colleagues, UCAM Professor Luiz Alberto Gómez de Souza and his wife Lúcia Ribeiro, both leading scholars and grassroots activists of the Catholic Church, organized the event. (Brazil is the world’s largest Catholic country.)

During my hour-long presentation in Portuguese, I recalled my family’s long fight against HD, beginning with my mother’s diagnosis in 1995, followed by positive test for the genetic defect in 1999 and the wrenching experience of testing our daughter Bianca in the womb in early 2000.

I felt deep relief after showing the audience pictures of our HD-free “miracle baby” in action as a youth soccer player. I spoke of the “double luck” we currently savor: Bianca will never face the terrible threat of juvenile HD, and I remain symptom-free despite having long passed my mother’s age of onset.

“At 55, my mother […] could no longer drive, she couldn’t work, she couldn't talk,” I said. “By a huge stroke of luck, I am healthy. Each day is a blessing.”

However, I also pointed to the many other bioethical challenges faced by HD families, including discrimination, family and caregiver stress, financial burden, and the lack of adequate facilities and caregiving personnel for late-stage patients.

The room became very quiet as I related how Carol Carr (of Georgia) in 2002 took a gun to the nursing home where her two HD-stricken sons lay helpless in bed and shot them dead to prevent further suffering. Carr spent nearly two years in prison.

“That was extremely sad for our community,” I recalled. “Huntington’s disease is not something easy to speak about.” 

With no effective treatments, such was the degree of hopelessness that has plagued the HD community, I had pointed out earlier.

The hope of clinical trials

“But I came to Brazil not to speak just about sadness,” I continued. “I also came to speak about hope and the promise of biotechnological research.”

The scenario for the HD community has changing radically in recent years with major advances in research and the advent of clinical trials to test potential remedies, I said.

I spoke of the immense potential revealed in the announcement last year of the gene-silencing clinical trial by Isis Pharmaceuticals, Inc. Citing an e-mail from Isis executive Frank Bennett, Ph.D., received the day before the presentation, I confirmed that the trial would start by year’s end.

(Indeed, the morning after my talk, Isis officially announced that it had commenced the trial.)

You can view my talk in the video below.

A Doença de Huntington, a Bioética e a Promessa da Biotecnologia from Gene Veritas on Vimeo.

A local commitment to the cause

During the Q & A, several Brazilian HD-affected individuals and caregivers spoke of their many struggles with the disease.

They also expressed excitement about the Isis clinical trial.

Carmen Paiva, Ph.D., spoke of her lab’s work in HD genetic and epidemiological research among Brazilian HD families. She told the audience of other local researchers and physicians focusing on the disease.

Recognizing common struggles

At the close of the session, Prof. Gómez de Souza evoked a key point of my presentation: the interconnectedness of neurological disease research and the common struggles of the afflicted.

He spoke with profound emotion about his brother, the renowned actor Paulo José Gómez de Souza, who has suffered from Parkinson’s disease for more than two decades but has successfully strived to continue working.

The struggles are shared among diseases – and among nations.

I look forward to celebrating with my Brazilian relatives and friends the defeat of HD, Parkinson's, and other neurological disorders as a result of a truly global effort.

Isis Pharmaceuticals launches historic clinical trial to silence Huntington’s disease gene

Isis Pharmaceuticals, Inc., based in Carlsbad, CA, has launched its long-awaited clinical trial to test a drug designed to attack Huntington’s disease at its genetic roots.

In a July 21 press release, Isis said it had initiated a Phase I human clinical study of ISIS-HTT_Rx, its compound aimed at diminishing the symptoms of HD. HTT_Rx signifies a medication for HD. The disease is caused by a defect in both the huntingtin gene and protein, which are symbolized by the letters htt.

“ISIS- HTT_RX is the first therapy to enter clinical development that is designed to directly target the cause of the disease by reducing the production of the protein responsible for HD,” the release stated.

In partnership with Roche, the Switzerland-based pharmaceutical giant sharing costs of the typically expensive clinical trial, Isis thus becomes the first entity to use a gene-silencing technique in the attempt to stop HD.

“Although the toxic protein produced from the huntingtin (HTT) gene in HD patients has been a target of interest for many years, no therapies have advanced to clinical trials to treat the underlying cause of the disease,” Frank Bennett, Ph.D., Isis’s senior vice president of research, stated . “Our antisense technology has enabled us to discover and develop ISIS-HTT_Rx, the first therapeutic approach designed to treat the genetic cause of HD."

Frank Bennett, Ph.D., of Isis Pharmaceuticals (photo by Dr. Ed Wild)

A ‘significant milestone’

HTT_Rx is an antisense oligonucleotide, an artificial strand of DNA created by Isis to block the action of the RNA molecules that translate the huntingtin genetic code to make the huntingtin protein.

Involving about 36 early-stage HD patients at about six sites in Europe and Canada, the Phase I trial focuses on the safety and tolerability of HTT_Rx. According to an Isis spokesperson, the sites will start recruiting participants as early as in a few weeks.

Depending on the pace of recruitment, Phase I most likely will end in 2017. If Phase I is successful, a larger Phase II trial to test efficacy likely would take place in 2018. A successful Phase II trial would be followed by a Phase III trial. Together all three phases of a clinical trial program typically take at least five years.

Last August, scientists from Isis and CHDI Foundation, Inc., the nonprofit virtual biotech firm that funded the early stages of the Isis research starting in 2007, provided extensive details about the plans for the trial. (Click here to read more.).

“The initial development of this antisense drug for Huntington’s disease came out of a longstanding productive partnership between Isis and CHDI, and its advancement now to clinical trial is testament to Isis’ perseverance and scientific expertise,” CHDI president Robi Blumenstein stated in the press release. “It’s exciting that therapeutic candidates grounded in the biology of Huntington’s disease are finally making their way to clinical trial.”

“The initiation of the ISIS-HTTRx study is a significant milestone in the history of Huntington's disease research as this marks the first time a drug designed specifically for Huntington's patients has transitioned into the clinic,” George Yohrling, Ph.D., senior director for mission and scientific affairs for the Huntington’s Disease Society of America (HDSA), wrote in an e-mail. “My hope is that this study not only shows that the drug is safe, but serves as an informative beacon for all future huntingtin-lowering trials.”

Martha Nance, M.D., the director of the HDSA Center of Excellence at Hennepin County Medical Center in Minneapolis and a member of the executive committee of the Huntington Study Group, said that “it would be impossible to overstate the importance of this trial.”

“I am old enough to have grown up in the 1960s, swept up as a young child with the excitement of space exploration, and I remember, almost as clearly and importantly as the Apollo 11 mission that actually LANDED on the moon, the Apollo 8 mission over Christmas 1968, during which William Anders took the iconic picture of the earthrise over the moon,” Dr. Nance wrote in an e-mail. “There were several more steps, several more Apollo missions, before Neil Armstrong could jump off the ladder onto the moon. The ISIS study is the HD equivalent of the Apollo 8 mission.”

LaVonne Goodman, M.D., the founder of Huntington's Disease Drug Works, said that there are "high hopes and expectations" about the trial. "We celebrate those individuals with HD, heroes who are selflessly participating in this trial and all others, 'taking one for the team,'" she wrote in an e-mail.

“We’re very enthusiastic about the drug,” Dr. Bennett said in a 2014 interview.

As he put it previously, Isis technology is like a “laser-guided missile” that targets a specific, disease-causing messenger RNA and destroys it or takes it out of the body “so that you don’t produce that messenger RNA.”

The Isis-Roche partnership

According to the press release, with the initiation of the clinical trial, Isis – a small company – earned a $22 million milestone payment from Roche. To date, Isis has earned $52 million in upfront and milestone payments from the partnership. It can earn more as the project progresses, as well as royalties on potential sales.

Roche can exercise the option to license ISIS- HTT_Rx from Isis through the completion of the Phase 1 trial. If so, Roche will assume responsibility for global development, the acquisition of regulatory approvals, and marketing the drug.

The partnership is critical. Isis cannot alone afford to carry out a clinical trial. Drugs usually cost hundreds of millions of dollars to develop.

According to the press release, Isis’s drug projects include 38 drugs aimed at treating a wide range of diseases, among them cardiovascular disease, metabolic disorders, cancer, and severe and rare diseases, including neurological disorders such as HD.

A huge dose of hope

The announcement of the historic trial’s launch provides a huge dose of hope for the HD community.

Since the discovery of the huntingtin gene in 1993, scientists have published thousands of research papers on HD and identified hundreds of potential “targets” for treatments.

In recent years, scientists and drug companies have initiated an increasing number of clinical trials in the quest for effective treatments. However, to date none has proven successful in halting the disease.

A necessary leap

As seen in animal studies, the infusion of HTT_Rx into the brain has led to the disappearance of the HD-like symptoms.

Scientists warn that it’s a still a huge leap from animals to humans when it comes to testing drugs. Also, only about one in ten clinical trials results in a drug reaching the market.

Earlier this year prominent HD specialist Bernhard Landwehrmeyer, M.D., Ph.D., cautioned that it could still take decades for the gene-silencing approach to play an effective part in managing the disease.

“We should all be extremely excited and hopeful, but remember that there is a lot of work ahead for researchers, doctors, patients, and families before we will get to our moon, and no guarantee of success,” wrote Dr. Nance.

Nevertheless, the Isis-Roche trial is a major step. At a minimum, it will help answer key questions about the gene-silencing approach.

If it is successful in ameliorating symptoms, it could mean the beginning of the end of Huntington’s disease as a threat to the tens of thousands of families affected worldwide.

* * *

Below see links to previous reports on Isis.

"Moving toward a potential treatment: Isis, CHDI researchers outline upcoming Huntington's disease gene-silencing clinical trial"

"A key new ally in the search for Huntington's disease treatments"

"Quickening the pace towards a Huntington's disease gene-silencing clinical trial: pharma giant Roche, Isis enter partnership"

"Designing the best drug possible to defeat Huntington's disease"

"Building a 'laser-guided missile' to attack Huntington's disease"

"Observing the cure in progress"

Also see coverage at HDBuzz by clicking here.

(Disclaimer: I hold a symbolic number of Isis shares.)

The Huntington’s disease community can’t afford to lose momentum

The Huntington’s disease community can’t afford to lose momentum in the quest for treatments for this incurable disorder.

As I noted in my last article, fatigue can set in for advocates and family members. This is understandable, given the tiring demands of caregiving, the frequent feelings of hopelessness in the face of the “devil of all diseases,” and the immense challenge faced by scientists – and the population needed to participate in drug trials – in devising revolutionary drugs that reach the brain and prevent its cells from dying.

Interrupting my own momentum in writing a book in my field as a Brazil specialist, I summoned the strength to once again focus on HD. I traveled coast-to-coast twice in a little more than 72 hours to give a speech about a crucial upcoming HD clinical trial and to interview a prominent scientist engaged in the search for treatments. It was an intense time.

My trip on April 10 began inauspiciously, as a late departure from San Diego caused us to approach Atlanta as thunderstorms struck, leading the flight to detour to Birmingham, AL. Arriving in Atlanta close to midnight, I had missed my connection to Providence. After finally finding a hotel 20 miles from the airport, I could only sleep four hours. The morning flight to Providence also left late, because of tardy pilots.

Travelers do face such stresses, especially as service in the airline industry declines, but as a carrier of the HD gene mutation concerned about disease onset, I especially need to avoid them.

As it became clear that I would miss my 9 a.m. keynote talk on April 11 in Norwich, CT, Laura Kokoska, an advocate for the Connecticut affiliate of the Huntington’s Disease Society of America (HDSA-CT) whose mother has HD, helped me via cell phone calls and texts to calmly consider alternatives. She and another advocate, Val Kim, whisked me from Providence to Norwich, serving me lunch in the car. We arrived in time for me to speak in the last slot of the day.

The audience of some 30 was anxious to hear me provide an HD family member’s perspective on one of the most significant steps towards treatments since the discovery of the huntingtin gene in 1993: the Roche/Isis gene-silencing trial, set to start this year at several sites in Canada, England, and Germany.

HDSA-CT education event participants (from left to right): James McGann, Debbie Pausig, Gene Veritas (aka Kenneth Serbin), Laura Kokoska, Holly Broadbent, and Sue McGann

A historic attack on the genetic roots

I first explained how my mother’s demise from HD and my positive test for the genetic mutation in 1999 led me to delve into the science of Huntington’s disease. Then I described how since early 2008 I have tracked the program by Isis Pharmaceuticals, Inc., to stop HD at its genetic roots. In 2013 Isis partnered with the pharmaceutical giant Roche to prepare for a gene-silencing clinical trial in HD.

“This trial is a historic trial,” I said. “It’s a big moment in the history of our community, and also in the history of science.”

Isis and Roche aim to test a drug known as an antisense oligonucleotide (ASO). “That’s a fancy term for basically saying it’s an artificial piece of DNA,” I continued. “That is [a] ‘laser-guided missile’ that is supposed to go into the brain cells, and it will block the production of the huntingtin RNA and the protein.[…] The protein is what is causing the problems in the cell. They’re also thinking now that the RNA is also causing problems within the cell, that they want to cut down the amount of the RNA, too.

“This clinical trial […] is the first time that someone is going after the genetic roots of the disease,” I stressed. “That is an immense motive for hope in our community.” And that’s why I’m so excited about the project and follow it so closely.

Being realistic

I showed PowerPoint slides of photos of the Isis facility and the company’s scientists, including Frank Bennett, Ph.D., the senior vice president for research and the head of the HD project. I also noted the important support for the project from CHDI Foundation, Inc., and the lab of Donald Cleveland, Ph.D., at the University of California, San Diego.

I reminded the audience that enthusiasm must be coupled with patience: the HD community must recognize the time it takes to develop drugs and also brace itself for failures in the quest for treatments. This year Isis and Roche are initiating Phase I of the trial, aiming only to test the safety and tolerability of the ASO.

Potential Phases II and III would examine the drug’s efficacy. In all, it could take five years or more to complete all three phases.

“We have to be realistic,” I said. “Ninety percent of drugs that go into clinical trials do not make it to market.[…] It takes a lot of shots on goal before you finally get a goal.[…] We have to keep in mind that it’s a slow, painstaking, and deliberate process.”

You can watch my speech in the video below.

Hope for Huntington’s Disease Families: The Isis/Roche Gene-Silencing Clinical Trial from Gene Veritas on Vimeo.

Returning to Yale

After the event I rode to New Haven with Debbie Pausig, a marriage and family therapist, grief counselor, and HDSA-CT support group leader. Debbie recently published An AffaiR Worth Remembering With Huntington’s Disease: Incurable Love & Intimacy During an Incurable Illness, a memoir of her relationship with her late, HD-stricken husband. Debbie capitalized the “r” in “affair” – and it’s reversed on the cover of the actual book – to emphasize the many unusual twists in her story.

Later I visited the campus of Yale University, my alma mater, and ate pizza at an old haunt. It was only the fourth time I’ve returned to Yale since graduating with a B.A. in history in 1982. In 2012 I visited Yale to interview a number of scientists working on HD (click here to read more), including the preparation of clinical trials.

“Felt like an undergrad again walking through freezing campus,” I texted an old classmate while watching the students and remembering the exhilarating possibilities of youth.

In my hotel room, mixing in baking soda and Epsom salt from a care package put together by Laura, I relaxed in a hot bath. As Laura put it, the bath would help my body recover from the traumatic plane trip.

Gene Veritas (aka Kenneth Serbin) outside Wall Street Pizza (formerly Naples) in New Haven

A science tour and lunch with old friends

The next morning I took a tour of Yale’s Magnetic Resonance Research Center with its long-time director, Doug Rothman, who received his Ph.D. from Yale in 1987. A professor of diagnostic radiology and biomedical engineering at the Yale School of Medicine, Dr. Rothman is one of the world’s leading pioneers in research in MRI, magnetic resonance spectroscopy, and quantitative neuroscience with magnetic resonance.

A future article will detail my interview with Dr. Rothman about his research into key questions about the mitochondria, the powerhouses of our cells, and their role in HD.

I lunched with classmate Paul Bass and his wife Carole (Yale 1983), two former colleagues on the Yale Daily News and accomplished journalists in New Haven. The Basses have long served as confidantes.  

Paul’s innovative online community newspaper, the New Haven Independent, was one of the first sites to link to this blog, and Carole blogged for the Yale Alumni Magazine about my definitive exit from the HD closet in 2012.

I welled with emotion at seeing my old friends, hearing good news about their lives and young adult daughters, and sharing my joy at having remained asymptomatic beyond my mother’s age of onset.

Paul and Carole Bass (photo by Gene Veritas)

Supporters of the HD cause

That evening in New York I dined with another Yale friend, Norman Oder (class of 1983), and his girlfriend Maryanne. A journalist, editor, and founder of the watchdog blog Atlantic Yards/Pacific Park Report, Norman urged me to start this blog and has edited virtually every piece since its inception ten years ago.

During my 24 hours in New York, Norman and I had several deep conversations about my future health, the destiny of this blog, and numerous aspects of the HD movement. He is my “HD alter ego.”

On April 13, I had lunch with yet another classmate, Adam Glick, a businessman and philanthropist who has generously supported the HD cause. Adam’s real estate company owns the Parker Palm Springs, the hotel in Palm Springs, CA, that expertly hosts the annual, CHDI-sponsored HD Therapeutics Conference when it takes place in the U.S.

I gave Adam a rundown of the 2015 conference, which I attended. We also discussed the “nocebo effect,” the idea that the expectation of illness can bring on symptoms even though a person is not ill.

I told Adam that last year two major supplements – coenzyme Q10 and creatine – thought to have potential for treating HD were proven ineffective. I speculated that my belief in these supplements’ efficacy might have contributed to my lack of symptoms.

Quiet resolve

At Maryanne’s suggestion, I visited the Museum of Modern Art (MOMA) to view the special exhibition of Jacob Lawrence’s series of paintings about the great migration of African-Americans from the rural South to the urban North in the mid-20th century.

This significant event in our nation’s history is forgotten by many. As a professional historian, I was both intrigued and moved by the tempera paintings depicting the hardships of African-Americans in the South and the brave decision by millions to uproot themselves to find a better life.

My teenage daughter, a first-year high school student, had asked me to take photos of murals in New York. I didn’t have time to search for murals, but Lawrence’s paintings are mural-like and tell a vast story. I will soon show them to her.

Visiting MOMA gave me a break from the HD-laden aspects of my trip. Yet I could not help but draw a parallel between the quiet resolve of the migrants and the yearning of the HD community for liberation from the yoke of Huntington’s disease.

Through such resolve we can maintain the momentum necessary for defeating HD.

The African-American South-North migration of the mid-20th century as depicted in one of the paintings of Jacob Lawrence (photo by Gene Veritas)

(I wish to thank the individuals and organizations that organized the conference and sponsored my trip: Sue McGann, HDSA-CT, and the Wireless Zone Foundation.)

(Disclosure: I hold a symbolic amount of Isis Pharmaceuticals stock.)