After many historic failures, if there is one disease that causes horror and fear not only to those afflicted with it, but also in the hearts of an industry wishing to banish it, it has to be Alzheimer's disease. Many big pharma players have tried to come up with the next big discovery, or a new causative mechanism for the disease, and even after a slew of candidate therapeutics made it to the clinic, here we are in 2016 with effectively no disease-modifying therapeutic for this brain-ravaging condition. It's a very tough fight I have had some experience with, having led a preclinical development program for a potentially disease-modifying candidate molecule, in my biotech past!
Alzheimer's disease drug development has literally become a graveyard of failure, with way too many patients heading to their graves barely remembering who they were, and that is a kind of personal hell and cruel robbery that must be an extremely traumatic way of exiting one's lifespan in this mortal coil. But although the rewards would be great (in both human and ROI terms), so equally devastating have the failures been that drug development in this area has become something of a "where (even) angels fear to tread" territory.
However, one glimmer of hope has been keeping the candle burning in recent years, and that is the BACE inhibitor category, and in particular, one in co-development at Eli Lilly who picked up the asset from AstraZeneca (AZ) when they were moving to limit their exposure in the Alzheimer's space. It was a $50M deal in 2014 that helped to carry the technology forward, whereby Lilly now has a 50-50 stake in the drug candidate as part and parcel of a deal that could reach half a billion dollars in value for AZ.
The teams have been firmly engaged in AMARANTH, a Phase II/III study of AZD3293, which is an oral beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitor currently under investigation. The recent interim safety analysis by an independent committee was not intended to measure efficacy; it was more a question of tolerability and safety concerns. There must have been a huge sigh of relief all around when that interim analysis revealed that the study could move forward with no modifications needed.
This means that the trial can now proceed into a full-blown Phase III study, and the companies have announced their intent to move more or less immediately into the DAYBREAK Phase III trial, where efficacy (in an early setting) will be a key front-and-centre factor. Additionally, they intend to recruit as many as 2,200 patients in some 14 countries to get the data they need to hopefully move this out into the marketplace. This success triggered a milestone payment of $100M from Lilly to AZ, who must be feeling some degree of acknowledgement for their previous efforts in discovery of AZD3293, today!
“Alzheimer’s disease remains one of the biggest challenges facing medical science today. BACE inhibitors have the potential to target one of the key drivers of disease progression and we are delighted that our combined efforts have resulted in the development of AZD3293 moving into the next phase of study. Disease modifying approaches, such as this, have the potential to transform the treatment of Alzheimer’s disease and help patients in this area of large unmet medical need.” said Menelas Pangalos, Executive Vice President, IMED Biotech Unit of AstraZeneca.
Lilly in particular have been feeling the heat in the AD space, having had their own BACE program which was halted over toxicity issues. Additionally, they ran into trouble with a gamma-secretase inhibitor drug candidate, Semagacestat, which actually had damaging effects at higher doses tested in the clinical trial. Further, they experienced yet another failure with Solanuzemab, a humanised mAb against a portion of the beta-amyloid peptide, and that candidate failed in two key Phase III trials, Expedition 1 and 2.
An unnamed ex-FDA official was quoted at the time as saying that "Solenuzemab does not have a snowball’s chance in a very hot place of getting conditional approval from the FDA", which sort of says it all about what happens after two failed Phase III trials. Lilly took some additional heat for stating that they would "move the goalposts" for Solenuzemab and lower the criteria that would define success, particularly with monitoring of early stage and presymptomatic individuals, and look for improvals in cognition.
It has been a most challenging if not downright uphill challenge for Lilly, but you know what? Kudos to them! Why? Well, because someone's gotta do it, and their persistence is precisely what is needed in the fight against this brutal disease, and if we need to try and try again to get it right, then fine! It will all have been worth it if any disease-modifying treatment comes online, and I have no problem at all with that company (or companies) reaping huge rewards as a result. Failure in the clinic is almost a given for Alzheimer's disease, as the failure rate is frustratingly close to 100% for over a decade or more.
Not that Lilly and AZ are entirely alone, having said that. Biogen is another company that has committed to continuing on in the space, and they recently partnered with Eisai on their BACE program, and both Merck and Novartis have their own candidates. One of the most fascinating things about all of these studies is their capacity to put to bed once and for all the possibility that the "BAPtists" had it right all along - and the beta-amyloid hypothesis of Alzheimer's disease hit it right on the head - but it was just a question of where to come at it from, that's all.
Let's hope that this is indeed the case because irrespective of whether one is a BAPtist or a TAUist, and whether amyloid plaques or neurofibrillary tangles are the major root cause of the disease, the sooner that patients can see any disease-modiifying therapeutic, the better. It's estimated that the prevalence of Alzheimer's disease is already nudging 50 million people worldwide, and in this aging population and era of longevity, that number is set to explode by even 2030.
Alzheimer's disease is one that has risen phoenix-like out of medical successes in other lifespan-limiting human ailments, but it's a success that came with a considerable price tag and one that has now placed a huge burden on the healthcare system of today. That cost is severely compounded by the human burden (patients, families and caregivers) inherent to the disease, and one has to hope that the flickering candle of hope that was brightened by the good news from Lilly et al. blossoms into a fully-fledged supernova of hope via their upcoming Phase III trials.
That may be a lot to ask for, and may be seemingly overly optimistic given all of the disappointments, but we have to remain firm in the belief that we can move on from the graveyard of failures (and deaths) and bring some new hope to the bedsides of patients with treatments that keep them living, and increase their quality of life as they struggle with this devastating disease.
The markets were a little less sanguine though, as the news did little in terms of share prices for either company, but you know, it's pretty hard to impress anyone with respect to Alzheimer's disease data these days, and it may take until some candidate actually proves efficacy in a substantial Phase III trial to get investors hot and bothered. Until then, fingers crossed!
The teams have been firmly engaged in AMARANTH, a Phase II/III study of AZD3293, which is an oral beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitor currently under investigation. The recent interim safety analysis by an independent committee was not intended to measure efficacy; it was more a question of tolerability and safety concerns. There must have been a huge sigh of relief all around when that interim analysis revealed that the study could move forward with no modifications needed.
This means that the trial can now proceed into a full-blown Phase III study, and the companies have announced their intent to move more or less immediately into the DAYBREAK Phase III trial, where efficacy (in an early setting) will be a key front-and-centre factor. Additionally, they intend to recruit as many as 2,200 patients in some 14 countries to get the data they need to hopefully move this out into the marketplace. This success triggered a milestone payment of $100M from Lilly to AZ, who must be feeling some degree of acknowledgement for their previous efforts in discovery of AZD3293, today!
“Alzheimer’s disease remains one of the biggest challenges facing medical science today. BACE inhibitors have the potential to target one of the key drivers of disease progression and we are delighted that our combined efforts have resulted in the development of AZD3293 moving into the next phase of study. Disease modifying approaches, such as this, have the potential to transform the treatment of Alzheimer’s disease and help patients in this area of large unmet medical need.” said Menelas Pangalos, Executive Vice President, IMED Biotech Unit of AstraZeneca.
Lilly in particular have been feeling the heat in the AD space, having had their own BACE program which was halted over toxicity issues. Additionally, they ran into trouble with a gamma-secretase inhibitor drug candidate, Semagacestat, which actually had damaging effects at higher doses tested in the clinical trial. Further, they experienced yet another failure with Solanuzemab, a humanised mAb against a portion of the beta-amyloid peptide, and that candidate failed in two key Phase III trials, Expedition 1 and 2.
An unnamed ex-FDA official was quoted at the time as saying that "Solenuzemab does not have a snowball’s chance in a very hot place of getting conditional approval from the FDA", which sort of says it all about what happens after two failed Phase III trials. Lilly took some additional heat for stating that they would "move the goalposts" for Solenuzemab and lower the criteria that would define success, particularly with monitoring of early stage and presymptomatic individuals, and look for improvals in cognition.
It has been a most challenging if not downright uphill challenge for Lilly, but you know what? Kudos to them! Why? Well, because someone's gotta do it, and their persistence is precisely what is needed in the fight against this brutal disease, and if we need to try and try again to get it right, then fine! It will all have been worth it if any disease-modifying treatment comes online, and I have no problem at all with that company (or companies) reaping huge rewards as a result. Failure in the clinic is almost a given for Alzheimer's disease, as the failure rate is frustratingly close to 100% for over a decade or more.
Not that Lilly and AZ are entirely alone, having said that. Biogen is another company that has committed to continuing on in the space, and they recently partnered with Eisai on their BACE program, and both Merck and Novartis have their own candidates. One of the most fascinating things about all of these studies is their capacity to put to bed once and for all the possibility that the "BAPtists" had it right all along - and the beta-amyloid hypothesis of Alzheimer's disease hit it right on the head - but it was just a question of where to come at it from, that's all.
Let's hope that this is indeed the case because irrespective of whether one is a BAPtist or a TAUist, and whether amyloid plaques or neurofibrillary tangles are the major root cause of the disease, the sooner that patients can see any disease-modiifying therapeutic, the better. It's estimated that the prevalence of Alzheimer's disease is already nudging 50 million people worldwide, and in this aging population and era of longevity, that number is set to explode by even 2030.
Alzheimer's disease is one that has risen phoenix-like out of medical successes in other lifespan-limiting human ailments, but it's a success that came with a considerable price tag and one that has now placed a huge burden on the healthcare system of today. That cost is severely compounded by the human burden (patients, families and caregivers) inherent to the disease, and one has to hope that the flickering candle of hope that was brightened by the good news from Lilly et al. blossoms into a fully-fledged supernova of hope via their upcoming Phase III trials.
That may be a lot to ask for, and may be seemingly overly optimistic given all of the disappointments, but we have to remain firm in the belief that we can move on from the graveyard of failures (and deaths) and bring some new hope to the bedsides of patients with treatments that keep them living, and increase their quality of life as they struggle with this devastating disease.
The markets were a little less sanguine though, as the news did little in terms of share prices for either company, but you know, it's pretty hard to impress anyone with respect to Alzheimer's disease data these days, and it may take until some candidate actually proves efficacy in a substantial Phase III trial to get investors hot and bothered. Until then, fingers crossed!
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