Antisense Oligonucleotides Enter Clinical Trials

Ionis Pharmaceuticals' HTTRx development team, from left to right: Roger Lane, Curt Mazur, Holly Kordasiewicz, Erika Paz, Kristin Balogh, Anne Smith, Tom Zanardi, Dan Norris, Eric Swayze, Tiffany Baumann, Kristina Bowyer, Gene Hung, Jose Mendoza, Frank Bennett (Not pictured: Gina Mc Mullen, Ed Wancewicz).

Ionis Pharmaceuticals’ HTTRx development team, from left to right: Roger Lane, Curt Mazur, Holly Kordasiewicz, Erika Paz, Kristin Balogh, Anne Smith, Tom Zanardi, Dan Norris, Eric Swayze, Tiffany Baumann, Kristina Bowyer, Gene Hung, Jose Mendoza, Frank Bennett (Not pictured: Gina Mc Mullen, Ed Wancewicz).



NAME: Ionis Pharmaceuticals


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Meet the team behind IONIS-HTTRx, the antisense oligonucleotide therapy with the potential to transform HD treatment

Ionis Pharmaceuticals has been developing antisense-based therapies for a variety of conditions since 1989. The company has developed an antisense oligonucleotide (ASO) that targets huntingtin messenger RNA. In July 2015, they began a first-in-man, Phase I/IIa trial on IONIS-HTTRx in early manifest HD patients to evaluate the safety, tolerability, and pharmacokinetics of intrathecal administration of the drug. HD Insights sat down with four of the individuals involved in the development of HTTRx to find out more. The following is an edited transcript of the conversation.

HD INSIGHTS: Dr. Kordasiewicz, tell us about the rationale for ASOs in HD and what you learned in animal models.

HOLLY KORDASIEWICZ: It is pretty straightforward. The idea is to go after the source of the disease, which we know is mutant huntingtin protein (mHTT). We can use ASOs to selectively lower huntingtin RNA, which reduces the total amount of huntingtin protein (HTT), including mHTT. By lowering mHTT in patients with HD, we can hopefully stop the course of the disease. With the work that we have done in animal models, we lower mHTT using ASOs, and some aspects of the animal disease—which are similar to what we see in HD patients—are reversed, and the animals begin to do better in a number of different ways.

These animal studies have been a collaborative effort with the group here at Ionis, Dr. Don Cleveland’s laboratory at UCSD, CHDI and also Genzyme, particularly Dr. Lisa Stanek, who was responsible for the work done in the YAC128 mice. We have looked at the R6/2 mouse, the YAC128 mouse, as well as the BACHD mouse.1,2 All of those mice express either fragments or the whole human mutant Huntingtin gene (mHTT).

HD INSIGHTS: How did you deliver the drug in the mouse models and how might that differ in humans?

KORDASIEWICZ: In human patients we deliver the drug intrathecally, directly into the cerebrospinal fluid (CSF), so that the drug can access the full brain. It is very difficult to do intrathecal delivery in mice because they are so small, so we use intraventricular delivery instead. We go into the mouse right lateral ventricle, which is just a little bit of a larger space so it is easier for us to access.

HD INSIGHTS: Two of the concerns with this approach are the potential need to give repeated injections and the possible need for allele selectivity. Could you comment on those concerns?

KORDASIEWICZ: When we started this approach, we did not realize how long ASOs and their effects last once you introduce them into the brain. About two weeks after we deliver the drug, we have maximum RNA reductions, and then those levels start to come back to normal. In mice, it takes about 12 to 16 weeks for levels to return to normal after a single injection, so in the human Phase I study we are trying monthly dosing. Eventually we could be looking at less frequent dosing, based on the characteristics of the drug.

ROGER LANE: The monthly dosing in the initial Phase I study is just to get concentrations up during the three-month dosing period.

KORDASIEWICZ: We spent a lot of time looking at allele selectivity. We did a collaboration, initiated by Dr. Frank Bennett, with Dr. Michael Hayden’s group to look at allele-selective approaches. The chemists here also worked with Dr. David Corey’s group at UT Southwestern, looking at using different antisense mechanisms to achieve allele selectivity. The work that I did in the mouse models examined the consequences of lowering only mutant human HTT, or both mutant human HTT and wild-type mouse Htt. In the mice, we found that we did not attenuate our benefits by lowering both the mutant human and the wild-type mouse protein; it was very similar to lowering just mutant human huntingtin alone. Because of that, we have gone forward with the nonallele-selective approach, but we have spent a lot of time working to find potential allele-selective approaches.

HD INSIGHTS: Did any safety issues emerge in your animal models?

KORDASIEWICZ: We looked at a number of endpoints and we followed animals for a year after dosing. We did not see any safety issues either in the wild-type mice or non-human primates resulting from lowering wild-type huntingtin.

HD INSIGHTS: Dr. Smith and Dr. Lane, what led you to determine that the drug was ready for study in humans?

LANE: Well, if you have a very good mechanistic rationale for a drug, support from good animal models of the disease, confidence that it can distribute to its target tissues and engage its target, and you have a means of measuring that target engagement, then you have a rational basis for a clinical development program.

HD INSIGHTS: Can you tell us about your Phase I/IIa clinical study?

ANNE SMITH: We can discuss it in general, but since it is ongoing, we will not discuss any data that is accruing. It is a small study, intending to enroll about 36 patients at sites in Canada, the UK, and Germany. We began dosing midyear, and the study is going well. Our sites are run by investigators at institutions who have been involved in helping us shape this program for many years. They are thought leaders in the area.

LANE: It is a multiple ascending dose study where patients are being treated with four intrathecal injections over a three-month period, then followed up for four months after that.

SMITH: Drug development is a long process. This is the first trial in humans, so we have planned several stops along the way where we have an independent group look at safety and help guide us if any changes are needed. So far, the study is proceeding according to plan.

HD INSIGHTS: From your listing, it seems that you are focusing on individuals with early manifest HD. Can you explain your rationale for that, and discuss the decision not to look at individuals with, for example, prodromal HD?

SMITH: Yes, we are indeed limiting participation in the study to early manifest patients. In later manifest HD patients, we had concerns about ability to consent. In prodromal patients, it would be a different sort of clinical development program. It is an area that we are very interested in going into, but if you are looking at patients who do not yet have motor symptoms, it changes the clinical endpoints that you would use in that study.

C. FRANK BENNETT: In this population, we felt the risk-benefit ratio was appropriate. We were concerned about enrolling individuals too early in the course of the disease in a first-in-man study. Without any experience with the drug in humans, we felt that the risk was too high for those patients. We identified individuals with early manifest HD as the ideal patient population.

HD INSIGHTS: What clinical endpoints are you looking at in this study?

SMITH: This first study is a safety and tolerability study, so the primary endpoints are a battery of safety endpoints. We are looking at a number of exploratory markers of disease in hopes of seeing a signal, but this is a short study in a small number of patients and it is certainly not designed, nor powered, to detect any changes in those types of endpoints.

LANE: We have a secondary endpoint to make sure that we are achieving the concentrations of ASO in the CSF that we are expecting, and then we are looking at target engagement whether we reduce mHTT in the CSF. We have a variety of other markers we are using to look at whether we are having a biological effect on the disease, including other CSF markers, EEG, neuroimaging, etc. We have some clinical measures, which we do not expect to be impacted in such a short-term study, but which we want to monitor for any deterioration. There is just a tiny chance that they could show something positive as well.

SMITH: These markers may also be useful in planning later studies if we see any small changes in this preliminary study.

HD INSIGHTS: I believe this will be the first clinical trial that investigates CSF markers. You mentioned that you are looking at mHTT in CSF. Can you talk about the reliability of CSF markers in HD and what you expect to find in the study?

SMITH: Well, there are challenges in being first. Assays for mHTT levels have been explored in several publications, and it is such a clear, obvious marker for our product and we are optimistic that we will be able to see changes with that marker.3,4 The other CSF markers we are using, such as neurofilament light chain and synaptic health markers, are definitely exploratory. Being first, we do not know what happens to these markers when you have modified the disease, so ask us when the study is over!

HD INSIGHTS: TRACK-HD and other studies have looked at brain volumetric MRI over time and found it has potential as a biomarker in HD. Are you looking at volumetric MRI or other outcome measures?

SMITH: We are looking at volumetric MRI, yes. TRACK-HD and other studies have given us beautiful natural history data that has helped a lot with our program and designing our study. Again, it is a short study, so we do not expect to see positive changes. We will use these markers primarily to assess whether there is deterioration in the trial participants.

HD INSIGHTS: For clinical assessments, you are using the HD Cognitive Assessment Battery (HD-CAB) developed by Dr. Julie Stout and colleagues. Are there other clinical measures that you are looking at, such as the Q-motor?

SMITH: The HD-CAB is our primary cognitive measure and again, being early, there really is not longitudinal data in that one either, so it will be interesting to see how that performs longitudinally. We do not have the Q-motor in the study.

HD INSIGHTS: When do you expect the initial results of the study to be available?

SMITH: We are on pace to meet the timeline we initially set, with a primary completion date of March 2017, and a study completion date of September 2017.

HD INSIGHTS: What has been the response of the HD community to the study? Have they been receptive? Was education required?

SMITH: We have wonderful support from our principal investigators. My understanding through them is that there has been a lot of interest in participating in the study, including “cold calls” from patients they know, to them and to us. Enrolling this study is probably not going to be a challenge because the community is very well educated about what is available to them now and what is coming. There is a lot of excitement around this product.

HD INSIGHTS: Are there other topics or questions that you would like to address related to your efforts?

BENNETT: Just that although our initial study is being done in Canada, the UK and Germany, subsequent studies would probably involve patients from more countries, including the USA. We are doing everything we can to accelerate the development, making sure that we are staying on track. And that if the drug is successful, we will start further studies as expeditiously as we can.

SMITH: I just want to remind people that it is a lengthy process and it is going to be a long timeline. There is a lot of anxiety in the community because people feel that they are missing something, even though its development has just barely started. Making sure we maintain realistic expectations is important.

HD INSIGHTS: What are your plans for future development should the initial studies go well?

BENNETT: We do not have very firm, locked-in plans, but the thought is that the next studies would test longer-term exposures with a larger group of patients, really Phase II studies.

LANE: The next studies may involve patients at earlier stages of HD. In addition, with this approach we can start thinking of prevention. At the moment, HD is diagnosed at the stage of clinical manifestations of brain pathology, but patients have had brain pathology developing for a long time before this stage. With genetic testing and the inevitability of the disease once the pathology has started, we have the prospect of going back to earlier points, when patients are not yet exhibiting symptoms, and treating them to prevent or delay the development of the disease. That may be some way in the future.

HD INSIGHTS: Thank you all for your efforts.

C. Frank Bennett, PhD: Dr. Bennett is the Senior Vice President of Research at Ionis Pharmaceuticals. He contributed his thoughts on the earlier stages of IONIS-HTTRx’s development to HD Insights, Vol. 3, and has continued to oversee this and other ASO programs at Ionis since that time.

Holly Kordasiewicz, PhD: Dr. Kordasiewicz is the Director of Neurological Drug Discovery at Ionis Pharmaceuticals, where she has worked since 2011 after completing her postdoctoral fellowship in the lab of Dr. Don Cleveland. She focuses on the preclinical development of novel drug candidates, investigating compounds in animal models and then characterizing the compounds prior to clinical development.

Roger Lane, MD, MPH: Dr. Lane is the Vice President for Clinical Development at Ionis Pharmaceuticals, a position he has held since January 2014. He leads clinical development efforts in the neurological therapeutic area at Ionis.

Anne Smith, PhD: Dr. Smith is the Director of Clinical Development at Ionis Pharmaceuticals, and serves as the Project Team Leader for IONIS-HTTRx.

1Kordasiewicz Holly B, Stanek Lisa M, Wancewicz Edward V, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron. 2012 Jun 21;74(6):1031-1044.

2Stanek LM, Yang W, Angus S, et al. Antisense oligonucleotide-mediated correction of transcriptional dysregulation is correlated with behavioral benefits in the YAC128 mouse model of Huntington’s disease. J Huntingtons Dis. 2013;2(2):217-28.

3Wild EJ, Boggio R, Langbehn D, et al. Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients. J Clin Invest. 2015 May;125(5):1979-86.

4Southwell AL, Smith SE, Davis TR, et al. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression. Sci Rep. 2015 Jul 15;5:12166.