Ryan Watts of Genentech is not only a researcher with a keen interest in the blood-brain barrier. He is also the founding research scientist on the clinical trial collaboration with the Alzheimer’s Prevention Initiative that NIH Director Francis Collins announced on May 15 at the 2012 NIA Research Summit in Bethesda, Maryland (see ARF related news story). Alzforum reporter Gabrielle Strobel spoke with Watts.

Q: In parallel to this upcoming prevention trial in autosomal-dominant Alzheimer’s disease that was announced yesterday, Genentech is developing crenezumab for late-onset AD. You are currently enrolling for a multicenter cognitive and a biomarker study in North America and Europe, both in Phase 2. In prior conversations, scientists at different pharma companies cited a perceived risk to their LOAD development program as a major reason for eschewing secondary prevention in a small population of mutation carriers (see ARF essay on prevention trials). How do you see this issue?

A: Therein lies the major reasoning behind crenezumab. We engineered this antibody to have reduced activation of microglia, the resident CNS immune cells. Our clinical studies thus far have shown no risk of vasogenic edema or microhemorrhage at doses in excess of other anti-Aβ antibodies. For us to move earlier in the progression of disease, the antibody needed to be safe. To go into a prevention trial where people do not have symptoms, it had to be very safe.

Recall that the origin of this field was active immunization marked by meningoencephalitis. Passive immunization has also been plagued by blood-brain barrier disruption seen as vasogenic edema and/or microhemorrhages. These observations have limited dosing and also raise concern about treating patients in a prevention setting. We have had the benefit of learning from these experiences. We engineered an anti-Aβ antibody that avoids these problems, and tested it in a large Phase 1 program that included ApoE4 carriers. We saw neither encephalitis nor vasogenic edema at relatively high doses, and thus feel motivated to do this prevention trial. We are enthusiastic about how important it is to go early and run a study like this. We also feel strongly about limiting patient risk.

Q: The other reason pharma was uninterested in the past is how long prevention trials in AD take. Five years!

A: If you have a defined genetic cohort and know when mutation carriers start to develop disease, then it becomes a different question. We are in it for the long run. We think this is a key clinical trial to test the amyloid hypothesis.

Q: Another argument I frequently heard is that trials in genetic mutations would not help get an indication for LOAD, the larger market.

A: Who knows what it means in terms of market size or labels? A purely commercial or purely regulatory perspective is not what drives us.

Q: Then what drives you?

A: Doing the right experiment. The concern is that researchers do their experiments in mild to moderate patients and, when those studies are negative, walk away, even though they never did the right experiment. Every biological pathway in AD will have an ideal time in the progression when that pathway is targetable. And there is no doubt that Aβ is a very early player.

We have an entire strategy for AD. We are going after several different molecular pathways besides Aβ. At this point in time, Aβ is a priority because of the genetic data, the clear runway, so to speak, of 10- to 15-year accumulation, and the availability of biomarkers. But as we go after cell death and neuroinflammation, for example, the concept that earlier is better does not automatically apply. Some pathways will likely be more active or targetable in later stages. Or consider the cholinesterase inhibitors or memantine, which are designed to enhance the function of the limited number of neurons that are still alive. It may not necessarily be better to take this type of drug in a preventive way.

Q: You have not thought about how the results of this API trial will affect registration for crenezumab?

A: It is too early to say if this type of study will allow us to make claims beyond this genetic cohort. Again, we run this study because it is the best scientific experiment to test the amyloid hypothesis in humans.

Q: How is crenezumab different from the other Aβ antibodies that are currently in Phase 2 and 3 trials?

A: We have a manuscript under review that describes its properties. Basically, crenezumab binds to oligomeric and fibrillar forms of Aβ with high affinity, and to monomeric Aβ with lower affinity. By comparison, solanezumab binds monomeric Aβ, and gantenerumab binds aggregated Aβ, as does bapineuzumab. Crenezumab binds all forms of the peptide.

Crenezumab is engineered on an IgG4 backbone, which allows it to activate microglia just enough to promote engulfment of Aβ, but not so strongly as to induce inflammatory signaling through the p38 pathway and release of cytokines such as tumor necrosis factor α. Crenezumab is the only IgG4 anti-Aβ antibody in clinical development that I am aware of. We have not seen vasogenic edema in our Phase 1 trials, which was the first main hurdle for us to overcome.

Q: Does that affect dose?

A: Yes. We can dose substantially higher than other anti-Aβ antibodies. For example, the bapineuzumab studies are dose-limited to 1 mg/kg as a result of vasogenic edema. Vasogenic edema resolved at 13 weeks. Hence, dosing for the Phase 3 was set at 1 mg/kg and 0.5 mg/kg once every three months in ApoE4 non-carriers, or 0.5 mg/kg in ApoE4 carriers. We are dosing as high as 15 mg/kg once a month. This generates a brain exposure that is between 10- to 100-fold higher. That is important.

By the way, one misconception along these lines warrants correction: Sometimes you read that solanezumab does not get into the brain, but bapineuzumab does. That is not true. Both get in at approximately a 1,000:1 ratio. In fact, most antibodies establish a steady-state ratio of approximately 1,000:1 blood-to-brain, unless they are uniquely engineered to cross the blood-brain barrier.

Bapineuzumab was the trailblazer to identify these risks. If you come into the field late, your goal is to engineer around these risks.

Q: The AD field is moving toward collaboration and data sharing. How about it?

A: This is part of the agreement with API. We are members of ADNI and understand the principle of data sharing. Data from this trial will be made publicly available.

Q: DIAN has a smaller number of asymptomatic carriers than does the API, and participants with dozens of different mutations in presenilin and APP, but is otherwise in a similar position. Are you interested in doing a similar thing with DIAN?

A: We are part of the DIAN consortium and believe all of these studies hold great promise.

This is Part 2 of a two-part series. See also Part 1.

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  1. I would like to thank Ryan Watts for a remark that is not directly linked to this very interesting project but that, nevertheless, I find important for the overall research landscape in AD:

    When he comments on the general trend for "going early," he is one of the few voices pointing out clearly that " ... the concept that earlier is better does not automatically apply. Some pathways will likely be more active or targetable in later stages."

    While his argument is mainly based on the need for optimizing the population to be studied with regard to the mode of action of the compound to be tested, there is a general aspect that should be considered in all cases: that the rate of decline is faster in moderate and severe stages of AD than in MCI or in cohorts for prevention trials should not be underestimated when it comes to designing development programs for new candidate drugs. Going too early may ruin studies via the need for long treatment periods (leading to high dropout rates) and large samples (leading to increased variability).

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References

News Citations

  1. NIH Director Announces $100M Prevention Trial of Genentech Antibody

Other Citations

  1. ARF essay on prevention trials

External Citations

  1. Ryan Watts
  2. Phase 2

Further Reading

News

  1. NIH Director Announces $100M Prevention Trial of Genentech Antibody