Beyond Bapi: Alzheimer’s Pipeline Runs Deep

With the failure of the second of four Janssen-led Phase III trials testing bapineuzumab, partners Janssen and Pfizer have elected to discontinue the bapineuzumab I.V. clinical development program. Nonetheless, the anti-amyloid-beta approach is still alive, as the field turns to early, pre-symptomatic intervention.

Johnson & Johnson and its partner Pfizer Inc. have one shot remaining at the once-promising bapineuzumab program; after discontinuing development of the intravenous formulation after two failed Phase III trials, they still have a Phase II trial ongoing of a subcutaneous formulation of the Alzheimer’s candidate.

That Phase II trial, SUMMIT AD, completed enrollment of approximately 120 North American patients in January. The study, which is looking at the drug’s effect on amyloid burden in the brain, is expected to report out final results in 2014.

Its clinical progression will likely hinge on results from the analysis of the placebo-controlled Phase III trials that constituted the bapineuzumab I.V. clinical development program. Tim Anderson of Sanford Bernstein speculated that Pfizer and J&J and Elan “will eventually take the SQ formulation into a Phase III pre-Alzheimer's population, contingent on the companies seeing positive biomarker data in Phase II.”

The companies announced on Aug. 6 that they were discontinuing the Phase III development program of I.V. bapineuzumab following the failure of a second Phase III trial (study 301) in patients with mild-to-moderate Alzheimer’s disease. The news comes on the heels of the July 23 announcement of the failure of the 302 study in APOE4 carriers to meet its co-primary endpoints.

The 301 trial tested the drug in patients who do not carry the APOE4 (apolipoprotein E epsilon 4) genotype. It failed to meet its co-primary endpoints: positive change in the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog), a measure of cognition; and positive change in the Disability Assessment for Dementia, a measure of function. While the companies made top-line data available, full results, including secondary endpoints and biomarkers, will be presented at the European Federation of Neurological Societies meeting on Sept. 11.

Some observers had speculated that, based on Phase II data in APOE4 carriers, the 301 trial might have a better chance of succeeding (Also see "Bapineuzumab Failure Raises More Doubts About Beta Amyloid Approach In Alzheimer’s" - Pink Sheet, 23 Jul, 2012.).

In addition to the 301 and 302 trials, both led by Janssen Pharmaceuticals Inc., Pfizer led two primarily ex-North American Phase III efficacy and safety studies in APOE4 carriers (study 3001) and non-carriers (3000). With the announcement, the Janssen Alzheimer’s Immunotherapy and Pfizer joint steering committee has decided to discontinue all bapineuzumab I.V. studies in patients with mild-moderate AD.

[Editor’s note: This story was updated to accurately reflect the bapineuzumab study numbers].

J&J stated in a press release that the company would record an after-tax, in-process R&D charge to earnings of between $300 and $400 million in the third quarter of 2012 related to the decision. Elan Corp. PLC, which initially developed bapi, perhaps stands to lose most. It partnered the drug with Wyeth and subsequently sold a majority of its share in the asset to J&J in 2009 in order to raise money to pay down debt (Also see "J&J And Elan Strike A Deal On Key Alzheimer's Disease Assets" - Pink Sheet, 6 Jul, 2009.). It is taking a $117.3 million impairment charge in the third quarter, but the real concern is that bapi’s failure leaves Elan heavily dependent on the multiple sclerosis drug Tysabri (natalizumab).

Regardless of this latest setback, interest continues in the anti-amyloid beta therapeutic approach. A public-private consortium that includes Roche’s Genentech Inc. recently announced that it would test Genentech’s Phase II anti-Aβ antibody crenezumab in a pre-symptomatic population harboring a genetic mutation that causes early-onset Alzheimer’s (Also see "Alzheimer’s Research To Be More Collaborative, Better Funded Under National Plan" - Pink Sheet, 15 May, 2012.). Early, pre-symptomatic intervention in the Aβ cascade – which could be the target of a Phase III for subcutaneous bapineuzumab – appears to be the way forward.

The Alzheimer’s pipeline is flush with large and small molecules, therapeutic and prophylactic approaches across numerous drug classes including anti-Aβ approaches, anti-Tau protein, vaccines, beta and gamma secretase inhibitors, neuronal nicotinic receptor inhibitors, histamine 3 antagonists, and 5HT6 antagonists (Also see "Beyond A-Beta: New Approaches To Alzheimer’s" - Scrip, 22 Jun, 2012.). Deutsche Bank AG, in a June Alzheimer’s report, surmised that roughly half the agents in development are anti-Aβ.

And Alzheimer’s remains a core therapeutic focus in the neuroscience divisions at J&J and Pfizer. Pfizer lists a passive immunotherapeutic and an oral 5HT6 antagonist in Phase I on its website, both inherited from Wyeth. The pharma speculates it might get a cognitive benefit administering the 5HT6 agent on top of Aricept (donepezil). In a recent J&J R&D presentation, Husseini Manji, therapeutic area head for neuroscience, listed an AD vaccine (vanutide cridificar), some oral amyloid and tau modulators, and the aforementioned Phase II subcutaneous bapineuzumab formulation.

The AD Pipeline: Selected Compounds In Phases I & II
This list is not comprehensive, especially with regard to Phase I candidates. It excludes some “natural” compounds that may be undergoing clinical testing. Of the 40-plus compounds included here, more than 50% target the amyloid mechanism, with an additional 30% representing novel symptomatic treatments for AD.
Anti-Amyloid-Beta Monoclonals
Compound	Developer	Phase	Estimated Time To Data Read Out
Bapineuzumab Subcutaneous	Pfizer/J&J/Elan	II	A Phase II clinical trial is underway in North America, known as SUMMIT AD. Final results from the study are expected in 2014.
Crenezumab	Roche	II	Currently undergoing two Phase II trials to evaluate intravenous and subcutaneous formulations. Data from both trials are expected in 2014.
Gantenerumab	Roche	II	The drug is a collaboration between Roche and MorphoSys. Results are expected in early 2017.
AAB 003	Pfizer/J&J/Elan	I	Initial results are expected in mid-2013.
BAN2401	Eisai	I	A Phase I trial was initiated in the U.S. in September 2010. Results are expected in 4Q 2012.
BIIB037	Biogen Idec	I	Initiated in June 2011, with final results expected to be released in 2012.
GSK-933776	GlaxoSmithKline	I	Currently in Phase II development. Phase I single and multiple dosing studies of ‘933776A in AD were completed in 2011.
SAR228810	Sanofi	I	A Phase I single and multiple dose-escalation study got underway in 1Q 2012, with results expected in 1Q 2014.
Anti-Amyloid Vaccines
Active immunotherapies for AD offer several potential advantages, including the likelihood that they will be cheaper and easier to implement over the long term if successful. Initial testing with the anti-amyloid AN-1972 vaccine was halted because of the development of aseptic meningoencephalitis in some patients. To avoid neuroinflammation and toxicity, new vaccines selectively target B-cell epitopes without stimulating T cells. Different adjuvants and mechanisms of vaccine delivery are being explored.
ACC001(PF5236806) Beta amyloid vaccine	Pfizer/J&J/Elan	II	Several Phase II studies ongoing, with results beginning to emerge by mid-2013.
Affitope AD02 N-terminal Aß peptide vaccine	GSK/Affiris	II	Currently being assessed over a one-year period, with trial expected to complete in early 2013.
CAD 106 Aß1-6 peptide vaccine	Novartis	II	Results expected by year-end 2012.
V950 Aß peptide Vaccine	Merck & Co.	I	Phase I safety and immunogenicity trial recently completed, with four years of follow-up.
Bace Inhibitors
β-site amyloid precursor protein-cleaving enzyme inhibitors have been shown to dramatically lower Aβ production levels. Development has been challenging, but several compounds in the class soon could be entering Phase II development.
LY2886721	Eli Lilly	I/II	A Phase I/II trial was initiated in March 2012. Results expected in late 2013.
AZD 3839	AstraZeneca	I	Developed in collaboration with Astex Pharmaceuticals. A Phase I trial was completed in November 2011.
E2609	Eisai	I	In March 2012, Eisai completed a Phase I study. Two additional Phase I studies are ongoing.
HPP 854	High Point Pharma	I	A Phase Ib study slated to complete in 1H 2012.
MK-8931	Merck & Co.	I	Phase I data evaluating the safety and tolerability of ‘8931 in 40 healthy adults were released in April, 2012. Two additional Phase I studies are ongoing.
RG7129	Roche	I	In January 2012, Roche completed a France-based Phase I. A U.S. Phase I study was to initiate in May 2012.
Gamma Secretase Inhibitors/Modulators
The fact that gamma secretase is involved in the cleavage of other important non-APP substrates has been a major issue in the development of gamma secretase inhibitors.
BMS 708163 (avagacestat)	Bristol-Myers Squibb	II	A Phase II study of 270 patients with prodromal AD is ongoing, with results expected by year-end 2013.
CHF 5074	Chiesi	II	Two Phase II trials underway.
E2212	Eisai	I	A Phase I single ascending dose study is underway.
Nicotinic Receptor Agonists And Antagonists
The α7 and α4β2nicotinic acetylcholine receptor (nAChR) subtypes are the most prominent in the central nervous system and are believed to mediate the pro-cognitive properties of nicotine. Targeting these receptors can provide symptomatic improvements in AD and may also have disease-modifying effects.
AZD 3480 (TC-1734)	AstraZeneca	II	A Targacept/AstraZeneca collaboration, this drug began a Phase IIb study in October 2011. Results expected in 3Q 2013.
AZD 1446	AstraZeneca	II	Phase II development of ‘1446 as an adjunctive treatment to donepezil in patients with mild-to-moderate AD is planned.
ABT-560	Abbott	I	Being developed by NeuroSearch in collaboration with Abbott. A Phase I trial was completed, but no studies are ongoing.
ABT-126	Abbott	II	Two Phase II dose-ranging studies, each in about 400 patients, were initiated in 1Q 2012. Results expected in 4Q 2013.
EVP-6124	EnVivo	II	A second Phase IIb trial initiated in April 2010 and completed in February 2012. Phase III development will begin based on Phase II results.
Serotonin Receptor Antagonists
Compounds in this class currently are being investigated for activity against serotonin 5-HT1, 5-HT4 and 5-HT6 receptors as adjuvant therapies in the symptomatic treatment of AD. There may be some potential for disease-modifying effects as well, as some preclinical data suggests that modulating serotonin signaling can enhance neuronal survival and functioning in the presence of beta amyloid.
LU AE 58054	Lundbeck	II	Phase II trial recently disclosed top line results Phase III development to move forward in the near term.
GSK-742457 (SB742457)	GlaxoSmithKline	II	Phase II trial as an add-on therapy to donepezil completed in August 2011. Five Phase II studies had mixed results. No trials are ongoing.
PF-05212377 (SAM-760)	Pfizer	I	Several Phase I studies have been completed.
ABT-354	Abbott	I	Phase I underway, Abbott has not specified what indications it will advance in Phase IIa studies expected to begin in late 2012 or 2013.
H3 Receptor Antagonists
Blockade of H3 receptors with selective antagonists can increase the release of neurotransmitters involved in cognitive processes, thus providing another avenue for the potential symptomatic treatment. H3 receptor antagonists have been shown to improve performance in a diverse range of rodent cognition models and also can increase wakefulness.
SAR 110894D	Sanofi	II	A Phase II trial in the U.S. is underway assessing cognitive performance. Final data are expected to be released in late 2012.
AZD 5213	AstraZeneca	I	Phase I studies completed. A phase II dose-ranging trial of ‘5213 vs. placebo in mild AD or mild cognitive impairment is not yet open for recruitment.
Other AD Candidates
ELND005 (Scyllo-inositol)	Elan/Transition	II	In May 2010, a Phase II completed. A long-term follow-up trial was completed in June 2011. Further development for AD remains on hold.
Ladostigil (dual cholinesterase/MOA-B inhibitor)	Avraham Pharma	II	Two Phase II trials results expected in 4Q 2012 and a three-year safety and efficacy trial results in late 2015.
ORM-12741 (a2C-adrenoceptor antagonist)	Orion Pharma	II	Seven Phase I trials and one Phase II trial ongoing. Results are expected in 4Q 2012
PBT2 (Metal protein-attenuating compound (chelator))	Prana	II	In December 2011, a Phase II trial initiated. A Phase IIa trial completed in 2008.
Rilapladib (LP-PLA2 inhibitor)	GlaxoSmithKline	II	A Phase IIa placebo-controlled study is enrolling, with completion slated in late 2012.
T-817MA (Neuroprotective antioxidant)	Toyama	II	In December 2011, Toyama completed a U.S.-based, Phase IIa trial which evaluated the efficacy of T-817MA (224mg, once-daily) in 373 AD patients to treat dementia.
Tideglusib (glycogen synthase kinase 3 inhibitor)	Noscira	II	In April 2011, Noscira initiated a Phase IIb trial. Initial results are expected in 3Q 2012.

Source: Deutsche Bank Market Research, “Alzheimer’s Disease: Is Help On The Way?,” June 2012