Saturday, December 16, 2017

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

After announcing December 11 that Ionis Pharmaceuticals’ gene-silencing drug for Huntington’s disease safely reduced the production of the toxic HD protein, company officials analyzed the firm’s successful Phase 1/2a clinical trial and discussed the next step: larger trials that are designed to test IONIS-HTTRx’s efficacy in alleviating symptoms by modifying the course of the disease.

I met with two lead scientists from Ionis’ HD team at company headquarters in Carlsbad, CA: Frank Bennett, Ph.D., Ionis senior vice president of research and the franchise leader for the company’s neurology programs, and Anne Smith, Ph.D., the Ionis director of clinical development and the individual responsible for the day-to-day management of the trial.

Drs. Bennett and Smith stressed that, because the two-year trial ended just last month, they could provide only an initial assessment of the results. The company plans to present detailed clinical trial findings at medical conferences in early 2018 and then publish the results in scientific journals.

Ionis will transfer administration of the next clinical trial phases to Roche, a key partner in the project since 2013. Roche now holds the license to IONIS-HTTRx, will lead further development, and handle all potential sales. Phase 1/2a took place in Canada, England, and Germany, but the next phase will have sites in the U.S. and other countries, to be determined next year by Roche. Ionis will continue to play an advisory role in the project.

“We are very appreciative of the community, and the patience that the community has exhibited,” Dr. Bennett said. “We understand how important this is for the HD community. We’re very pleased it’s going forward. The community has been very respectful towards the company and has allowed us to conduct this study in a way that was very robust.”

Drs. Bennett and Smith focused on how the trial revealed a reduction in the mutant huntingtin protein that “substantially exceeded our expectations,” according to the December 11 press release. The key, initial piece of trial data came from the measurement of the protein in the HD patients’ cerebrospinal fluid (CSF). Other trial data such as brain scans and blood samples will become available later.

IONIS-HTTRx and other Ionis drugs are antisense oligonucleotides (ASOs, artificial strands of DNA), which alter the expression of genes. In August 2016, Ionis and its partner Biogen actually halted a Phase 3 trial of an Ionis ASO in infants with spinal muscular atrophy (a motor neuron disease) because the drug was extending their lives. The FDA (Food and Drug Administration) approved the drug, with the commercial name SPINRAZA, in December 2016.

In October, Ionis and Biogen won a biotechnology prize for SPINRAZA (click here to read more). Ionis is also collaborating with Biogen to develop a drug for amyotrophic lateral sclerosis (Lou Gehrig’s disease).

Dr. Frank Bennett (left) with Gene Veritas (aka Kenneth P. Serbin) and Dr. Anne Smith (photo by Kristina Bowyer, Ionis)

Following are key excerpts from the interview.

Compelling changes in mutant huntingtin levels

GV: How did patients react to the intrathecal administration of the drug, that is, via a spinal tap?

AS: We didn’t hear from any of the physicians that there were any difficulties. There was probably some nervousness, but there were few side effects, and that ones they had were manageable. I think it’s telling that all 46 patients completed the trial.

GV: What was observed in the HD patients in this trial?

AS: We’re still in the process of getting these next waves of data in. That will come out over months. It’s important to recognize that the trial just ended in November. But at this stage we did see a promising safety profile, meaning that we didn’t have any clinical concerns with the drug.

We saw clear, compelling changes in mutant huntingtin levels in the CSF. It was sort of gravy in this study. It’s designed as a safety study. We didn’t know when we entered the study whether we’d be able to even measure mutant huntingtin in CSF. But it is the best evidence of target engagement that we have – meaning that it is evidence that the drug is doing what it ought to do.

We were pleased that the assay [lab test] was developed to the point that we could use it to measure mutant huntingtin. The test is relatively new and fortunately came online at about the right time that we needed it.

The label from the first vial of the Phase 1/2a clinical trial, administered in London, September 2015 (photo by Gene Veritas)

GV: The reductions of mutant huntingtin “substantially exceeded” your expectations. To what extent?

FB: When we began the program with Roche, we picked a target level of reduction of mutant huntingtin in CSF, and, based upon that, we would decide to go forward with the program [into the next phase].

We put the mutant huntingtin data at the top of the list, because it was the data that was going to drive a business decision from Roche, but also, importantly, it was the data that would help them design the next study. So we prioritized that as being the first thing we would look at. It’s the basis for telling us what are the doses that we should be using for the next study.

GV: So can you specify the amount of mutant huntingtin reduction?

FB: We’re going to save that for a medical meeting.

Phase 1/2a too early for improving symptoms

GV: You project from your pre-clinical animal studies that the level of reduction in the brain itself should be greater than what is seen in the CSF, correct?

FB: Yes. An important nuance for the community is that the level of reduction that we’re seeing in CSF is not a one-to-one correlation with the level in [brain] tissue, which is where you want the drug to be working. We haven’t proven it in patients, but we’re very confident that it will translate [into higher levels of reduction in the brain].

AS: We’ve tested this drug in several species and are able to understand that relationship between what you see in CSF versus what you see in [brain] tissue, which is why it was really important this assay [CSF measurement] was online. It really is a window into the brain.

To understand that relationship in animals, the animals have to be sacrificed, to measure the level in the [brain] tissue. So we won’t ever ‘prove’ it in humans, so to speak, but we have a good understanding of it through the animals. And that it’s consistent from species to species is comforting. We can draw a conclusion about what’s likely happening in the human.

GV: Many in the HD community want to know: in this trial, did you see any signs of disease modification? Were there any hints at all from the doctors or from the data?

AS: We get anecdotal reports from physicians, but this is a population with a high placebo effect. These are motivated and excited physicians and patients as well. So I wouldn’t read anything into that. It’ll be several months before we have an understanding, though I would really caution any expectations along those fronts, because this is a short-term study.

We’re not expecting to see any sort of disease modification, just because of the way the study was designed. We dosed for three months, but it wasn’t even full drug effect for three months, because you build up the effect. This is the precursor to what would be long-term dosing.

GV: Have you observed whether there was also a reduction in the wild type (normal) huntingtin protein that all HD patients also have?

FB: There isn’t a good assay [lab test] for measuring wild type at this point. We have the samples, and once the assay is robust enough, we’ll look at it. The team is working on it, as well as others.

GV: Were there any surprises in the data that you’ve seen so far?

FB: It’s only surprising that it’s worked as we predicted it would [laughter]. Oftentimes when you go from pre-clinical to clinical, things don’t quite work out as well. But the drug is doing what it should be doing, which is lowering mutant huntingtin in cerebrospinal fluid. I think it’s all very positive from that perspective.

Phase 2 versus Phase 3

GV: What have you learned that will be helpful in planning phase 2?

FB: We asked a lot of the sites and the patients – because we collected a tremendous amount of data from them – for data that will be useful in designing a Phase 3 trial. We wanted to figure out which of the clinical outcome measures, which of the imaging measures, is actually reproducible, robust, and sensitive, to make sure it’s not “noisy” data.

AS: Another important learning will be whether there are differences from site to site. In a multi-site, multi-country trial, if a particular test just doesn’t translate well to German, for example, then we’ll have learned that. We can spare Roche from collecting data that are difficult to interpret, because they’re difficult to operationalize across sites and countries.

GV: You said “Phase 3” and not Phase 2. Why?

FB: Yes. At this point, Roche has not made a final decision on the next step. One of the options being considered is going right to a Phase 3 study. There’s a trade-off. You can do a smaller Phase 2 study – get more data that make it more probable that you’ll be successful for the Phase 3 – or you can go directly to a Phase 3 study. Those are the decisions that Roche is looking at right now very carefully.

The plus side is: if they go right to Phase 3, it would accelerate getting the drug to market. When we’ve reviewed with them the size of the study and the time of the study, there’s not a big difference between doing a Phase 3 and doing a more traditional Phase 2 first. It’s more expensive to go right to Phase 3, but it would save a lot of time.

GV: For an entity such as the FDA, is it okay to go from a Phase 1/2a to a Phase 3?

FB: The FDA will pay a lot of attention to the safety of the drug which – so far, knock on wood – looks very good. And then they leave it to the sponsor whether they want to risk the program. They may advise – because they ultimately want the drug to be successful, too – that this isn’t the best thing to do, but ultimately that’s the drug company’s decision. Roche will engage with the FDA.

GV: What is leading Roche to think it could maybe go directly to a Phase 3?

FB: It’s safety and tolerability [shown in Phase 1/2a], and the fact that we now know what dose of the drug produces this level of huntingtin lowering. Without that, they wouldn’t be able to go to Phase 3, but with that data, you could say that “this dose” should then produce “this level” of huntingtin lowering.

GV: Going straight to Phase 3, how much shorter would the whole program be?

AS: It’s definitely in the years.

FB: Yes, because if they were to do a Phase 2 study first, it would probably take three years to enroll and run. Roche wants to get this drug to patients as quickly as possible, assuming it works. They understand the disease. They understand the need for the patients.

GV: Whether Phase 2 or 3, when would the next study begin?

FB: I would anticipate towards the end of next year.

An important milestone

GV: What is the historical significance of the Ionis breakthrough?

FB: It’s an important milestone for the Huntington’s community. The mutation in the huntingtin gene was described in 1993. This is the first drug to go into clinical trials that is directly on target. It addresses the cause of the disease. We’re extremely excited that we’re actually seeing this basic science and all the work that NIH and other agencies have funded over the last 25 years now being translated into something that could actually have an impact for Huntington’s patients.

This bodes well for other neurological diseases. It has potential to markedly change how we treat those diseases. Perhaps this technology platform [the Ionis gene-silencing approach] would be beneficial for them as well. For patients out there overall, this is extremely important.

(For additional information about next steps in the IONIS-HTTRx program, click here for a Q & A with Dr. Ed Wild, an advisor and investigator of the program. You can also read a FAQS from the Huntington's Disease Society of America by clicking here.)

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

(In the video below, watch my report on the December 11 Ionis announcement.)

Monday, December 11, 2017

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

In an initial clinical trial that marks a significant step toward finding an effective Huntington’s disease treatment, the Ionis Pharmaceuticals gene-silencing drug safely reduced the production of the toxic mutant protein implicated in HD, the firm announced today.

Ionis has handed development of the expected Phase 2 trial to its partner in the project, the multinational pharmaceutical giant Roche, earning a $45 million license fee, today’s Ionis press release stated. The drug is called IONIS-HTTRx: “HTT” stands for both the huntingtin gene and the protein it produces, and “Rx” signifies a remedy.

The trial was officially classified as Phase 1/2a. A Phase 1 trial measure’s a drug’s safety and tolerability in a small number of participants, while a Phase 2 trial examines efficacy in a larger group of patients. Though mainly Phase 1, this trial had elements of a Phase 2: actual HD patients took part, and it sought to determine whether the drug’s basic mechanism worked.

“We are encouraged by the performance of IONIS-HTTRx in the Phase 1/2a clinical study,” Frank Bennett, Ph.D., Ionis senior vice president of research, stated in the release.

The reductions of the mutant protein “observed in the study substantially exceeded our expectations,” Dr. Bennett added. The study, which involved 46 participants with early HD symptoms, did not assess whether that reduction slowed disease progression.

Ionis stated that “dose-dependent reductions of mHTT were observed” in the trial: the higher the dosage, the greater the reduction in the amount of the mutant protein.

“We were equally encouraged by the safety profile of the drug,” Dr. Bennett stated.

“The results of this trial are of ground-breaking importance for Huntington’s disease patients and families,” stated Dr. Sarah Tabrizi, professor of clinical neurology, director of the University College London’s Huntington Centre, and the global lead investigator on the Phase 1/2a study. “For the first time, a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well tolerated. The key now is to move quickly to a larger trial to test whether IONIS-HTTRx slows disease progression.”

Frank Bennett, Ph.D. (above, photo by Kristina Bowyer, Ionis) and Dr. Sarah Tabrizi (below, photo by Gene Veritas)

Pharma giant Roche steps in

Ionis officials stated in June that a Phase 2 study could start as soon as 2018. Typically, all three phases of a clinical trial project take at least five years, although nobody can predict the actual course of a trial.

In 2013, Ionis, a mid-sized drug-discovery firm that does not produce or sell drugs or conduct clinical trials on its own, partnered with Roche, one of the world’s largest and most successful pharmaceutical companies (click here and here to read more). Roche’s expertise includes neurodegenerative brain diseases.

Roche will now take over the development of IONIS-HTTRx, including the Phase 2 and potential Phase 3 trials and bringing the drug to market. It will hold the license to the drug.

Roche also will administer the open-label extension of the Phase 1/2a study, announced in June, whereby all patients – including those who got a placebo – will continue to receive the drug. The extension allows researchers to gather more data, examine the drug’s effects over a longer period of time, and better prepare for Phase 2. Patients also potentially benefit by receiving the drug longer.

Phase 2 to include United States

By attacking Huntington’s disease near its genetic roots, IONIS-HTTRx could potentially reduce, partly reverse, and even prevent symptoms. Ionis drugs are antisense oligonucleotides, artificial strands of DNA. The drug aims to turn off the huntingtin gene messenger RNA that contains the instructions to make the huntingtin protein in brain cells.

Forty-six patients took part in the Phase 1/2a trial at sites in Canada, Germany, and England.

“Today is an exciting day for the Huntington’s disease community,” a joint Ionis-Roche letter to the HD community stated. “Future studies for the program will be conducted globally, including in the U.S. Roche will announce details about future studies, including eligibility criteria and planned start dates, as this information becomes available.”

More than a decade of research

IONIS-HTTRx resulted from more than a decade of research involving Ionis, Roche, the lab of neurobiologist Donald Cleveland, Ph.D., at the University of California, San Diego, and CHDI Foundation, Inc., the nonprofit virtual biotech firm aimed solely at finding (and funding) HD treatments.

On December 3, Dr. Cleveland received the $3 million Breakthrough Prize, the world’s richest science award, sponsored by Google, Facebook, and other entities. It is twice the value of the Nobel Prize. Dr. Cleveland received recognition for his career contributions to the life sciences, including work on a cause of Alzheimer’s disease. (Click here to read more.)

Dr. Cleveland was honored at the 2012 gala of the San Diego Chapter of the Huntington’s Disease Society of America. For a recent article explaining the Dr. Cleveland’s role in the Ionis project, click here.

In interviews today, I hope to obtain further details about the progress regarding IONIS-HTTRx.

HDBuzz’s take: a historic breakthrough

The HD research site HDBuzz, produced by scientists, stated that today’s announcement is “likely to stand as one of the biggest breakthroughs in Huntington’s disease since the discovery of the HD gene in 1993.”

The site’s article, written by Jeff Carroll, Ph.D. – an HD-gene carrier like me and a scientist dedicating his career to finding HD treatments – asserted that the “most exciting” part of today’s news is that “dose-dependent reductions of mutant huntingtin were observed.”

The clinical trial administrators know this because they examined samples of participants’ cerebrospinal fluid, which runs along the spine and into the brain. Participants received injections of the drug via a spinal tap.

“This means that patients treated with IONIS-HTTRx have reductions in the huntingtin protein in their cerebrospinal fluid,” Dr. Carroll wrote. “Based on this result, it looks like the drug is doing what it’s meant to do, and that huntingtin lowering has been achieved!”

Dr. Wild concluded: “This is a great day in the HD community, and it sets us on the path to even more exciting work in 2018. For the first time in history, HD patients are being treated with drugs known to reduce the amount of huntingtin protein in their brain. Until we conduct the next trial, we won’t know if this reduces the impact of HD. And while we know the drug is safe in the short term, we will also have to watch carefully for any long-term adverse effects. But we’re facing this problem with renewed excitement and hope. It’s the best early Christmas present we could have hoped for.”

Jeff Carroll, Ph.D., at the 2012 CHDI-sponsored HD therapeutics conference (photo by Gene Veritas)

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