- Alzheimer's Dementia is a terrible and costly disease and currently the treatments for it are poor.
- Solanezumab and PBT2 have both shown that they may help the cognitive decline seen in Alzheimer's Dementia.
- Solanezumab and PBT2 both need further data from phase 3 trials to confirm efficacy.
- PBT2 should be able to fund a phase 3 trial by raising capital or partnering with a larger pharmaceutical company.
- A disease modifying drug in Alzheimer's Dementia is the Holy Grail for big pharma.
PBT2 and Solanezumab are both treatments targeting patients with Alzheimer's dementia. Their aim is to delay the onset of severe dementia in these patients and therefore improve their quality of life and ability to stay in their own homes.
In this article I will be analyzing the differences between Eli Lilly's (NYSE:LLY) Solanezumab and Prana Biotechnology's (NASDAQ:PRAN) PBT2 -- the new leading candidates in the treatment of Alzheimer's dementia and the implications for their development.
Funding for clinical trials
Solanezumab is one of LLY's great hopes for helping it to overcome its patent cliff. LLY has already completed two phase 3 trials of Solanezumab, Expedition 1 and 2 with a 3rd trial in the pipeline. It has experience bringing drugs to market and has the capacity to drive sales if Solanezumab is approved.
Even with the recent run up in share price the market capitalization of PRAN is still only $456m with approximately $20m in cash. It is in no position to fund PBT2 through large phase 3 trials without bringing a large pharmaceutical company on board or raising significant amounts of capital.
Management has no experience running large clinical trials and has not brought any drugs onto market. It is simply not feasible that PRAN with <20 employees would be able to drive a global roll out of PBT2 efficiently if it were approved.
A deal with a large pharmaceutical company is the most obvious answer to these problems but management would be wise to lock in whatever deal is negotiated as there was previously an interested party who pulled out after the onset of the global downturn in 2008.
Mechanism of action
Western medicine prides itself on practicing evidence based medicine in determining how best to treat patients. There are many levels to this evidence with the most robust being a well conducted randomized controlled trial. Unfortunately patients included in these trials are rarely representative of the general population.
Expert opinion is a much lower level of evidence but because of the heterogeneity of patients and clinical presentation there is still much art in determining how patients should be treated. The problem with art is its subjectivity and in the medical field this often equates to what the boss thinks should be done.
Expert opinion is often not much better. Flecanide was previously given to patients with heart attacks. This was done as there is scar formation on the heart post a heart attack and aberrant electrical conduction. Flecanide is an anti-arrythmic drug and cardiologists believed that giving it would prevent these episodes from happening.
Flecanide did indeed stop these premature ventricular complexes from developing. The only problem with this was that after a proper randomized controlled trial was conducted, it found that the use of flecanide led to increased mortality.
At this point you are probably wondering what this has to do with Solanezumab and PBT2. The link is that Solanezumab as a monoclonal antibody against beta amyloid targets one of the dominant theories of Alzheimer's dementia development, the amyloid cascade theory.
Amyloid plaques are seen in patients with Alzheimer's dementia but there is no clear correlation between the amount of amyloid plaque and its severity. Like Flecanide, Solanezumab may remove the beta amyloid but this may not actually help the patient.
LLY was not alone in its attempt to target beta amyloid. Bapinezumab funded by Pfizer (NYSE:PFE) and Johnson & Johnson (NYSE:JNJ) both failed phase 3 trials. Other failed attempts at targeting beta amyloid include Elan's beta amyloid vaccine AN-1792, Axonyx's phenserine which decreased beta amyloid production, Myriad Genetics (NASDAQ:MYGN) Flurizan which decreased beta amyloid through a direct effect on gamma secretase and another LLY drug Semagacestat a gamma secretase inhibitor.
PBT2 has an entirely different mechanism of action. It is an ionophore taking metals such as copper and iron from areas of excess (around the amyloid plaques) to areas of deficiency (the other neurons in the brain).
These metals are required for normal neuronal function but become trapped and form toxic oligomers in patients with Alzheimer's dementia. By liberating the metals from these areas PBT2 decreases their toxicity and helps promote normal neuronal function by bringing them back to where they are required.
In this model the amyloid plaques form secondary to the toxicity of the metals and hence are a symptom of the problem, not directly pathogenic in and of themselves.
Trial evidence to date
Solanezumab has completed two phase 3 trials, Expedition 1 and 2. 2052 patients were recruited into these trials and there was no significant benefit seen from the administration of Solanezumab. In a sub-group analysis of patients with mild Alzheimer's dementia LLY showed a 34% slowing in cognitive decline. Expedition 3 is designed to test this theory that Solanezumab needs to be given early in the course of Alzheimer's dementia to have benefit.
A further criticism of Expedition 1 and 2 and its negative result was that patients were not screened as to the levels of amyloid plaques in their brain. Some of the patients recruited may not have had a significant plaque burden and hence Solanezumab would not have been of benefit.
I have discussed in more detail here about the results of the PBT2 but in summary it showed a dose dependent improvement in executive function in its phase 2a trial. Its phase 2b IMAGINE trial is a proof of mechanism of action trial that is due to report this month.
Figure 1. Phase 2a results for PBT2 showing a dose dependent improvement in executive function.
Size of addressable market
Solanezumab has already failed in its previous phase 3 trials and hence now has a smaller target population, namely patients with mild Alzheimer's dementia. The ageing population and the prevalence of Alzheimer's dementia means that this would still be a blockbuster indication as millions of people could potentially end up taking Solanezumab until their dementia progressed.
PBT2 has yet to reach phase 3 trials but like Solanezumab it also seems to have more benefit in patients with mild Alzheimer's dementia. This does not mean that PBT2 would not work in patients with more severe dementia and it also has shown some activity in patients with Huntington's disease. To read more about the results of PRAN's phase 2 trial of PBT2 in Huntington's disease please follow this link.
Neurodegeneration is the holy grail for pharmaceutical companies but the success rate has been very low. This has led to the FDA giving guidance that they have lowered the bar in terms of the efficacy they would expect before they would approve a drug for Alzheimer's disease.
We will have to wait until the results of Expedition 3 to see if Solanezumab works in patients with mild Alzheimer's dementia. LLY was willing to fund this trial because it knows that the rewards will be rich if it were to be successful.
For PRAN success for PBT2 would be phenomenal for its share price. It would also see the metals hypothesis added to the list of quirky ideas like Helicobacter Pylori causing ulcers and the Human Papilloma Virus causing cervical cancer backed by Aussies that turned out to be true.
That day is still far away for PBT2 but with the impending release of PRAN's IMAGINE trial results the goal is now in sight. PBT2 has likely has shown enough efficacy to date to warrant the funding of a phase 3 trial but we will have to wait until the IMAGINE trial results are in.