Could Probiodrug Represent A New Era Of Alzheimer's R&D Progress?
Executive Summary
Probiodrug believes it can bring success to an Alzheimer's research community that has been hard hit by clinical failures in the last few years – but the company will need a partner or cash influx to take its first-in-class drug through late-stage trials.
"We cannot be held responsible for the failures of the past," said the professor leading Probiodrug AG's clinical program for novel Alzheimer's therapy PQ912, a glutaminyl cyclase (QC) inhibitor that is about to enter Phase IIb studies in Europe.
Philip Scheltens, a professor of neurology at the VU University Medical Center in Amsterdam, has a long-standing history within dementia clinical research in general and within Alzheimer's disease in particular. He is leading clinical studies for Probiodrug's QC inhibitor – which represents a new, first-in-class approach to treating Alzheimer's disease.
Prof. Philip Scheltens
In an interview with Scrip, he discussed the progress made by Probiodrug so far with PQ912 – which is being developed as a treatment for early-stage Alzheimer's disease – and the next steps for this drug candidate as it progresses into larger clinical trials.
Glutaminyl cyclase, an enzyme target discovered and patented by Probiodrug, has a crucial role in the pathogenesis of Alzheimer's disease as well as various peripheral inflammatory diseases. The company has completed a Phase IIa trial in 120 patients, which reported positive safety data and a noticeable efficacy effect on cognition (an exploratory endpoint). Now it is preparing to move the compound into a much larger Phase IIb study, which will have cognition as the primary endpoint.
There are no other companies with QC inhibitors in the pipeline so Probiodrug is trailblazing in this space. However, Eli Lilly & Co. is developing an early drug candidate for Alzheimer's based on a similar mode of action.
Probiodrug reported a cash position of €11.7m as of Sept. 30, 2017; while this is enough to fund the business through 2018, it will require additional capital to complete Phase IIb development of PQ912.
Analysts at Rx Securities expect the company to sign a licensing deal for its lead compound to pursue Phase IIb and Phase III trials. Potential partners are likely to be big pharmas or big biotechs that have the R&D budget to conduct costly large-scale studies in a high-risk area like Alzheimer's. "Unless a licensing deal for PQ912 is signed, the company will need to raise significant additional capital to fund further development of PQ912 as well as financing other projects," the analysts said in a Jan. 2 note.
Rx Securities analyst Dr Joseph Hedden told Scrip a company like Lilly, which has an active Alzheimer's pipeline and experience in the space, would be top of the list of potential partners for Probiodrug. He noted though that other big pharmas could be in the picture for a possible partnering deal, and a partnership for PQ912 is not beyond the reach of some mid-sized drug developers.
Rx Securities analysts estimate that if successfully developed, PQ912 could achieve peak sales of $5bn. Highlighting investment risks around Probiodrug, the analysts said that while the company's novel technology is promising, so far there were limited efficacy data from clinical trials. "We would also highlight that the company’s key development programs are based around similar hypotheses and there could therefore be multiple failures if these hypotheses prove inaccurate," they said.
Rx Securities expects that if PQ912 is successful in the clinic it could see a first launch in 2024.
Alzheimer's Stumbles At A Glance
The Alzheimer's research community has been hit by numerous late-stage, high-profile clinical setbacks in recent years and no new product has reached the market since 2002.
The most recent example of a large-scale failure in Alzheimer's came from Axovant Sciences Ltd. The company debuted on the public markets in 2015 with the biggest IPO ever for a biotech but its stock took a beating in September last year when intepirdine, a selective 5-HT6 receptor antagonist, failed to show a benefit in mild-to-moderate Alzheimer's patients in the Phase III MINDSET clinical trial. Axovant then ended all development of intepirdine in Jan. 2018 after the drug failed to report positive date in another dementia trial. The CNS-focused company is now floundering as it has little else in its pipeline to attract and keep investors. ( (Also see "Axovant's Cupboard Is Bare After Lead Dementia Program Fails" - Scrip, 9 Jan, 2018.))
In Feb. 2017, Merck & Co. Inc. ended the Phase II/III EPOCH clinical trial of BACE inhibitor verubecestat in mild-to-moderate Alzheimer's disease based on lack of efficacy. ( (Also see "Another Nail In Amyloid Hypothesis Coffin? Merck Ends Pivotal BACE Inhibitor Study" - Scrip, 14 Feb, 2017.))
And in Nov. 2016, Eli Lilly & Co.'s investigational therapy solanezumab failed to meet its primary endpoint in a third Phase III trial. The 18-month long EXPEDITION3 trial included more than 2,100 patients diagnosed with mild dementia due to Alzheimer's.
These examples highlight the misfortune Alzheimer's R&D has suffered in just the last couple of years. The sector is in dire need of a breakthrough and Probiodrug thinks it is on to a winner.
Alzheimer's disease, the most common form of dementia, is a severe neurodegenerative disorder characterized by a progressive loss of cognitive function. It is predicted that the disease will affect more than 80 million people worldwide by 2050.
A Fresh Approach
Alzheimer's drug development over the last decade has focused on drugs targeting beta-amyloid plaques in the brain. But with little success to date, researchers are seeking other approaches within this hypothesis.
Inge Lues, chief development officer at Probiodrug
"Amyloid beta plaque was considered a key element in inducing the disease but a decade of research, and also of failures, in the Alzheimer's community brought about a modified and more granulated concept," chief development officer at Probiodrug, Inge Lues, told Scrip. "The focus is no longer on the plaque itself, but on soluble pre-plaques called Abeta oligomers."
"The target Probiodrug is pursuing and the drug they have developed is very promising because it is a little bit out of the box by focusing on neurotoxic oligomers and not targeting plaques," Scheltens added.
Probiodrug is developing product candidates to target pyroglutamate-Abeta (pGlu-Abeta) in patients with Alzheimer's. PGlu-Abeta has been shown to be toxic to synapses and neurons, they interfere with the function and structure of synapses. "Impairment of synapsis are causally related to cognitive impairment. So, the theory is to inhibit the production of pGlu-Abeta, which will reduce the formation of the toxic abeta aggregates," Lues explained.
Probiodrug’s innovative approach comprises the development of specific inhibitors for the enzyme QC, which is instrumental in the creation of pGlu-Abeta. PQ912 is the company's most advanced QC inhibitor.
"What we learnt in the Phase IIa study, is that it is possible in a very short time frame to at least detect signals that the drug is active in the brain and protecting synaptic function," Scheltens said. The company has presented the Phase IIa findings recently at a scientific conference following the trial's completion in 2017. Scheltens added that it was very important to take next steps to develop the compound.
"We have biological and functional evidence of target engagement that needs to be corroborated in the next trial and also over a longer period of time," he said. Probiodrug will now extend the time that patients will be exposed to the drug and attempt to confirm the cognitive signals on attention and working memory that were seen in the first trial.
The Phase IIb trial program will include a trial in Europe, designed to provide longer-term efficacy data and guidance on dose tolerability of PQ912 in early Alzheimer's patients and a complementary study in the US (which is in the planning phase). Further updates on the designs and timelines of these trials are expected in the first quarter of 2018.
Lessons Learned
Talking about lessons Probiodrug has learnt from failures by other Alzheimer's drug developers, Scheltens said: "Not all drugs have the right targets, not all drugs have a lot of target engagement and a lot of trials were not designed to target the proper populations."
"This is all looking back of course, but you can explain many of the failures in retrospect," Scheltens said.
Scheltens said the chance of being successful in Alzheimer's now was bigger than before. While there are no guarantees, he thinks Probiodrug can use past examples to better its development programs.
Despite Scheltens' optimism for success at Probiodrug, some analysts are wary of the company's big talk based only on early safety data. "Given the amount of failure among Alzheimer’s drugs, it is wise to be inherently cautious, especially when it comes to new, invalidated drug targets," Datamonitor Healthcare's lead CNS analyst Daniel Chancellor told Scrip.
Chancellor was also skeptical over how much Probiodrug could learn from companies that have tried and failed to develop new therapies. He highlighted that Probiodrug has had PQ912 in clinical development for a long time; the company was presenting its preclinical data back in 2010. He also said it was not possible to say whether PQ912 was more sophisticated than other amyloid approaches. "With the amount of time it has been in clinical development, a lot of the discovery research for the drug was done prior to the major failures of gamma secretase modulators and the first-generation amyloid antibodies," Chancellor noted.