BACE Inhibitors Barrel Forward—Next Hurdles: Safety, Efficacy

Series - International Conference on Alzheimer's & Parkinson's Diseases 2013:

Read a PDF of the entire series.

After more than a decade of seemingly pushing against a wall, BACE inhibitors for Alzheimer’s disease are finally surging forward. At the 11th International Conference on Alzheimer’s and Parkinson’s Diseases, held 6-10 March 2013 in Florence, Italy, several pharmaceutical companies provided sunny updates on their candidate drugs, which have all shown the ability to dramatically lower Aβ in the cerebrospinal fluid (CSF) in Phase 1 trials. Most of the drugs have been tested only on healthy volunteers to date, but notably, Merck presented Phase 1 data from AD patients. Their compound was as effective in lowering Aβ in this population as it had been in the healthy controls, said Merck’s Mark Forman. The talks represented but a handful of the companies with inhibitors currently in Phase 1 or 2, which at this point all appear to look similar. In Florence, academic and pharmaceutical researchers alike expressed optimism that targeting BACE1 could be a viable therapy.

“I am impressed by how well BACE inhibition is working,” Michael Willem at Ludwig Maximilians University, Munich, Germany, told Alzforum.

Nonetheless, two significant challenges remain. One persistent concern bruited by many academic researchers is whether BACE inhibitors will prove safe enough for long-term use. Most Phase 1 trials have been brief, meaning that subtle adverse effects might not have had time to develop. A second unknown is whether lowering BACE1 activity will actually slow cognitive decline, especially in people who already have AD. Some researchers suggested these drugs may be more effective as a preventative, and worried that a negative clinical trial in AD could cause companies to give up on the drugs prematurely.

BACE1 Inhibition Effective in AD Patients, Too
Merck previously reported that its BACE inhibitor MK-8931 lowered CSF Aβ by 90 percent or more in healthy volunteers in a short Phase 1 trial (see ARF related news story). In Florence, Forman added data from a seven-day trial of 32 mild to moderate AD patients at three U.S. sites. This is an important step because people with AD, unlike most healthy volunteers, have a head full of amyloid, and that could change their drug response. Participants had a mean age of 73 and Mini-Mental State Examination score of 22, indicating mild AD. They received doses of 12, 40, or 60 mg daily. There were no serious adverse effects, with participants most commonly reporting dizziness, or headache and back pain related to the lumbar punctures, Forman said.

The results were consistent with those seen in healthy volunteers, with CSF Aβ40 and Aβ42 plummeting by up to 84 percent at the doses tested, Forman reported. “That helps us build confidence that we are hitting our target in patients, too,” he told Alzforum. “The major focus of this study was to understand the dose response in patients to help support our dose selection, because we do not have formal Phase 2 data to base dosing on.” Simulations from a disease model Merck built showed that at 12 mg, almost all patients will experience at least a 50 percent reduction in Aβ, and at 40 mg, 75 percent, Forman said.

Merck will take these three doses forward into its Phase 2/3 trial in patients with Alzheimer’s dementia, Forman said. This trial will be the largest yet for a BACE inhibitor, with 200 participants in Phase 2 and 1,800 planned for Phase 3 (see ARF related news story). The company also plans to test its inhibitor in prodromal AD patients, but will wait to see the safety data from the ongoing Phase 2 portion of this current trial, Forman told Alzforum. Other scientists at AD/PD expected that second, prodromal trial to start toward the end of 2013.

The Bright Side: All Signals Go From Early Trials
Eli Lilly’s inhibitor LY2886721 is also currently in a Phase 2 trial of 130 people with AD. In Florence, Patrick May described Phase 1 data he previously presented at the Alzheimer’s Association International Conference 2012 (see ARF related news story). Fourteen days of daily dosing slashed BACE1 activity by 50 to 75 percent, and CSF Aβ42 dropped 72 percent, May said. Robert Lai at Eisai Pharmaceuticals had similar data from a multi-dose Phase 1 study of their inhibitor E2609. As reported at AAIC 2012 (see ARF related news story), a two-week trial lowered CSF Aβ by 50-80 percent.

AstraZeneca did not present trial data in Florence, but Samantha Budd, of that company’s Cambridge, Massachusetts site, told Alzforum that a Phase 1 single-dose study of their inhibitor AZD3293 will wrap up in summer 2013. The company plans to release preclinical data at AAIC 2013 in Boston, Budd said. In Florence, Budd provided a tantalizing tidbit at the satellite imaging pre-conference, reporting that plaques shrank in six-month-old Tg2576 mice treated for one month with another of their BACE inhibitors AZ4217. At this age, the animals are actively depositing amyloid.

“BACE1 [inhibition] has been the Holy Grail since the first description of Aβ release,” May said, expressing a common theme. “Now we have a real shot at testing the amyloid hypothesis with BACE inhibitors.” Forman pointed out that, because this approach targets amyloid production at its point of inception, it should suppress both plaque formation and soluble oligomers. Therefore, the therapy could work regardless of which of these is the toxic entity.

The Dark Side––What Could Go Wrong?
With the new drugs getting into the brain and strongly lowering Aβ, a main concern now for many researchers is whether chronic treatment will lead to side effects. BACE1 cleaves numerous proteins. For many of its substrates, other enzymes can pick up the slack, but for some, BACE1 is the major sheddase, Willem said. One such protein is neuregulin 1, which plays a crucial role in myelination of axons (see ARF related news story; ARF news story; ARF news story). “In animals treated with [Lilly’s BACE inhibitor] LY2811376, we observe robust accumulation of [uncleaved] neuregulin 1,” Willem told Alzforum. However, May said in his talk that Lilly has not seen any reduction of neuregulin cleavage in vivo. Other scientists said that the dose needed to cause neuregulin accumulation exceeds that used in people, but all agreed the issue bears watching.

BACE1 knockout mice are outwardly fine, but upon closer examination show subtle defects in axon guidance (see ARF related news story). They are also more prone to symptoms resembling schizophrenia and to epileptic seizures (see ARF related news story). Additional substrates have been identified in screens by Stefan Lichtenthaler at the German Center for Neurodegenerative Diseases, Munich, and Bart De Strooper at the University of Leuven, Belgium (see ARF related news story). A recent study by De Strooper and researchers in Florida found retinal pathology in one strain of BACE1 knockouts (see Cai et al., 2012), but in Florence, Lichtenthaler reported he could find nothing wrong with the retina in a different strain. One caveat all sources agreed on is that even though the field at large refers to these drugs as “BACE1 inhibitors,” most of the current compounds act about equally potently on BACE2, meaning that BACE2 substrates must also be evaluated.

Researchers said it is difficult to predict how problems with myelination or axon guidance would manifest themselves in a clinical trial. “To be prudent, these companies ought to be doing a whole battery of tests that sample a range of behaviors: cognition, memory, neuropsychology,” suggested Robert Vassar at Northwestern University, Chicago, Illinois. “I would monitor vision and balance as well. Companies should cast a wide net, because we really don’t know what we’re going to see.”

Lichtenthaler agreed that pharmaceutical companies may want to look for a range of neurological and vision deficits. Because BACE1 promotes developmental processes like myelination, and some of these programs can be reactivated for repair after injury or brain trauma, BACE inhibitors might be ill advised for people who have recently fallen or hit their heads, he added. Despite this, Lichtenthaler told Alzforum, “I’m relatively optimistic at this point that the BACE inhibitors will not have too many side effects.” Pharmaceutical inhibitors never completely block protein activity, and would be given late in life. Thus, they should produce milder effects than those seen in knockout mice, which completely lack the protein from birth, he said.

How Much and When?
The question of how much to quell the enzyme looms large. The current compounds achieve up to 90 percent drops in Aβ production, but several academic researchers privately wondered if that might be too much for chronic treatment. “We are far away from fully understanding the impact of a BACE1 block on peripheral and central nervous system functions, but a medical treatment should definitely not result in a complete inhibition of BACE1 activity,” Willem told Alzforum. “Since BACE1 is upregulated twofold in AD, a reduction to its normal levels would be hopefully achievable and probably safe.” Lichtenthaler agreed, “My gut feeling is that if you reach somewhere around 50 percent inhibition, that would already be very good.”

However, Vassar told Alzforum, “Our best guess is that we’re going to have to inhibit at more than 50 percent of BACE, because the heterozygous BACE knockouts still make 90 percent of the normal amount of Aβ. I think we may have to inhibit 70-80 percent of BACE. That still leaves 20-30 percent of BACE around to perform the normal functions. I’m hopeful that we can achieve a therapeutic dose that balances efficacy with safety.”

Last summer’s discovery of a naturally occurring, protective APP mutation has shown that a lifetime dip of about 20 percent in Aβ production significantly protects against AD (see ARF related news story). “That helps us take an educated guess at the key question of how much amyloid reduction you need and how much is safe,” May said. For a treatment started late in life, when people already have plaque in their brains, however, stronger intervention might be needed. Budd suggested, “If we can safely inhibit at higher levels, perhaps that’s good in this late stage of disease.”

Merck’s current Phase 2/3 trial is enrolling people with mild to moderate AD, and they indeed chose doses that inhibit Aβ production by 90 percent. Some researchers worry that this approach could set the drugs up for failure. “I’m skeptical that Merck will see an effect in mild to moderate AD, even at 90 percent inhibition,” Vassar told Alzforum. At that stage of the disease, people already have been losing synapses and neurons for some years. Even if BACE1 inhibition prevents the formation of toxic Aβ oligomers, cognition may not improve, he speculated. Lichtenthaler concurred. “It may be the trial will fail because the patients are not doing much better. But maybe these are really great drugs and it’s simply that they were taken too late. I think [the drugs] would perform much better in prevention trials,” Lichtenthaler said.

Pharma scientists said privately that they suspect Merck knows this and has already decided to keep developing its inhibitor even if patients in the current trial prove too advanced to benefit clinically. Biomarker and safety data to help plan earlier-stage trials, as well as to establish drug effect and safety data across the entire spectrum of this disease, may represent enough gain to run a trial at the stage where, to date, most anti-amyloid drugs have failed (see also ARF Q&A With Merck’s Johan Luthman).

Likewise, Willem believes that a BACE inhibitor alone may do little to lower pre-existing plaque load. The solution may be to use a combination therapy. “After Aβ vaccination in an early stage of the disease, a mild BACE1 block could additionally control Aβ synthesis,” he suggested. Interest in combination therapy is growing in the AD field (see ARF related news story).—Madolyn Bowman Rogers, with reporting by Gabrielle Strobel.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. Wave of New BACE Inhibitors Heading to Phase 2
  2. Merck Launches Largest Trial of BACE Inhibitor in AD
  3. Madrid: BACE Found to Have Big Job in Wrapping Motoneurons
  4. Double Paper Alert—A Function for BACE, a Basis for Amyloid
  5. Neuregulin/ErbB4 Mutant Mice Have Myelin, Synaptic Deficits
  6. Not the Usual Suspects: Tracking BACE Inhibition, Axon Role
  7. Off BACE: Lack of Secretase Causes Seizures in Knockout Mice
  8. BACE Secrets: Newly Identified Substrates May Regulate Plasticity
  9. Protective APP Mutation Found—Supports Amyloid Hypothesis
  10. Q&A With Merck’s Johan Luthman

Paper Citations

  1. Cai J, Qi X, Kociok N, Skosyrski S, Emilio A, Ruan Q, Han S, Liu L, Chen Z, Bowes Rickman C, Golde T, Grant MB, Saftig P, Serneels L, De Strooper B, Joussen AM, Boulton ME. β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO Mol Med. 2012 Sep;4(9):980-91. PubMed.

Other Citations

  1. Read a PDF of the entire series.

External Citations

  1. Phase 2/3 trial
  2. Phase 2 trial
  3. Phase 1 study

Further Reading

News

  1. Q&A With Merck’s Johan Luthman
  2. Rounding Second BACE: Another Route to Memory Loss?
  3. Q&A With Roche’s CNS Leader Luca Santarelli
  4. Paper Alert: First BACE Trial Published—New Inhibitor On Deck
  5. Barcelona: Out of Left Field—Hit to The Eye Kills BACE Inhibitor
  6. Wave of New BACE Inhibitors Heading to Phase 2
  7. Merck Launches Largest Trial of BACE Inhibitor in AD
  8. Madrid: BACE Found to Have Big Job in Wrapping Motoneurons
  9. Double Paper Alert—A Function for BACE, a Basis for Amyloid
  10. Neuregulin/ErbB4 Mutant Mice Have Myelin, Synaptic Deficits
  11. Not the Usual Suspects: Tracking BACE Inhibition, Axon Role
  12. Off BACE: Lack of Secretase Causes Seizures in Knockout Mice
  13. BACE Secrets: Newly Identified Substrates May Regulate Plasticity
  14. Protective APP Mutation Found—Supports Amyloid Hypothesis
  15. Combination Drug Trials: Time to Open a New Front in AD?
  16. Tau, α-Synuclein Spread: Crazy Stuff—How Might It Work?
  17. Like Star Born of Supernova, Plaque Born of Exploded Neuron?
  18. Can Dousing PyroGlu-Aβ Treat Alzheimer’s Disease?
  19. Field Ramps Up "Mini" Mouse MRI
  20. LRRK Watchers’ Eyes Turn to Inflammation, Autophagy, Kinase
  21. Can Cancer Therapy Be Neurodegenerative Wonder Drug?
  22. Taking Aim at M1: Old Hat or New Target?
  23. Dementia in Movement Disorders: What Causes It?

Annotate

To make an annotation you must Login or Register.