Epilepsy Pipeline Update: Portal into CNS Opportunities

Epilepsy Therapy Project Conference, San Francisco
March 13, 2008

Please note these are rough notes I took at the conference. I intend to use this to help build out a living reference on the epilepsy pipeline that will live in the epilepsy.com wiki. I will advertise on this group as soon as I have created the first entry into the wiki. I invite everyone in the group to help edit and build out a comprehensive section in the wiki on the pipeline.

Warren

RNS, Neuropace, Martha Morrell

• Safe and Well Tolerated
• Growing evidence for efficacy
• Candidates 50% of those whose partial seizures are not well controlled

Q&A

• What about a shifting sz focus?
o Don’t anticipate that to be common.
o Could move leads
• Flexibility of stimulation parameters
o Many options and wonderful to have them
• One pivotal trial? Yes one
• Sz Detection algorithm
o Look at frequency, similarity of waveform,
o Detection problem is solved.
o May require a couple of iterations but ability to customize very powerful
• Does patient recognize stimulation?
o Can stimulate with patient perceiving.

Neurovista: John Harris, NeuroVista Seizure Advisor System

• 40 people in Seattle
• Can predict sz acitivty 10’s of minutes or even hours before sz onset.
• Believe the system will fundamentally change the paragdigm of how we treat patients.
• Fear and uncertainty responsible for much of the debilitating aspect of epilepsy…people spend little actual time seizing even with 3-4 sz’s per month.
• Device collects 16 channels of eeg data and transfers to handheld device
• Ability to warn patient of impending seizure (Red Light)
• Ability to provide Green Light signal in which seizures highly unlikely.
• Also Yellow Light for indeterminate state
• Challenges
o Can clinically meaningfull algorithm performance be achieved
o Have 20 terrabytes of intracranial eeg
o Data challenges and computational challenges.
o 400 microprocessor core supercomputer to answer questions.
o Statistical method challengens
• Can a practical system be built?
o Yes
• IP
o Two full time ip patent attornies
• May be means of adjusting chronic intervention, enable acute intervention

Q&A
• Audio alert?
o Yes visual, audio.
• Insurance Reimbursement
o Optimistic
o Should allow more people to work and engage in life, good economics
• Audience
o 2-12 seizures per month initially
o Ultimately valuable for people with less seizures than that.
o For daily seizures, may not be useful until we have ability to intervene acutely

Sierra Neuro, Dan Abrams,

• Dedicated to neuro-psych patients refratory to conventional therapies
• Through direct admin to the brain
• Epilepsy, depression, bipolar
• Based on work done over 20 years for pain in over 250k patients.
• IP Status: deep inventory of existing non-proprietary neuo durgs reformulated for direct delivery. Broad
• First FDA meeting May for epilepsy drug.
• Clinical trial design a challenge. Treatment paradigm shift.
• Medtronic support…only available pump
• Felbamate first drug: can avoid liver metabolism.
• Several other candidates: Clanozapine for med refract schizophrenia next candidate.
• 90 day dosing
• Will be raising money in next months

Q&A
• Intraventricular delivery: organ specific
• Have you explored intrathecal delivery
• Do you expect to avoid a black box?
o No. But commercially we do not think that will be an issue. Hope we can practically avoid those issues.
o Lots of patients and docs positive about this approach.

Neuromed: Elizabeth Tringham, PhD

• Oros Hydromorphone, 1/day oral opiod for pain most advanced
• N-type program, Merck partnership
• T-type program: acute and chronic pain, epilepsy
• T-Type calcium channels clinically important in epilepsy
• Leading patent position against others including Merck.
• Goal is to develop subtype selective T-type calcium channel blockers with improved safety and efficacy for epilepsy.
• Dilantin and Zarontin both have T-type activity.
• Animal target validation
o Collaboration with Jeff Noebels at Baylor
o Genetic models with spontaneous seizures
o Absence as well as generalized seizure models.
o Benchmark against Kepra and diazepam: 3 compounds outperformed Keppra and DZP.
• Next milestone is IND to do Tox work

Q&A

• No evidence that T type mutations cause genetic epilepsy in humans?
o Can show efficacy in threshold seizure models as well as mouse genetic models.
• Thoughts on absence epilepsy mkt?
o Smaller so want also to show efficacy in partial epilepsy
• Tests in kindling
o Hope to do them.

Icagen, Greg Rigdon, ICO 1065
• Rational for KCNQ modulation
o New moa, activity across range of preclin assays
o Genetic link to epilepsy
o KCNQ channels control membrane potential and excitability
o Opening KCNQ channels hyperpolarizes neurons, resulting in decreased action potential firing and therefore dampening of seizure activity.
o In epilepsy neurons fire too fast and too many at the same time, opening KCNQ channels act as a brake
o Works in animals:
o Prevents seizure spread (MES)
o Increases sz threshold PTZ
o Protects against generalized seizures 6 Hertz
o Good Oral availability
o BID dosing
o High tolerability in preclin testing
• Hope to start with patients this summer; maybe in photosensitive trials
• Ten US Patents and patent apps including composition of matter and use.

Q&A

o Cardiac effects?
o No. we look at KCNQ 1 and have a lot of selectivity against cardiac channels.
Biolink: Jens Tempe, Dynamin Inhibitors

o New MOA: recycling of synaptic vesicles needed for perpetuation of seizures.
o No existing drugs hit this target.
o Inhibition of dynamin inhibits neurotransmitter vesicle loading
o We are a research institute, not a biotech company
o Have 24 classes of Dynamin inhibitor,
o 3 selected lead classes
o Have shown 6 hz efficacy only.
o Doing more studies with NINDS
o Have filed 6 families of patents, growing IP estate
o Challenges:
o Need to partner with epilepsy focused biopharma
o Applicable to other CNS and cancer indications: screening ongoing.

Q&A

o Selection of lead candidates
o Done by outside experts, typical criteria
o What library did you screen?
o What side-effects might you expect? What is the normal role of synaptic recycling?
o None shown so far.

NeuroGenomix: 2DG: Tom Satula

o Supported by Wharf
o NeuroGenomeX focuses on neuroplasticity and changes in response to seizures.
o 2DG varies from sugar by a singe oxygen atom
o Efficacy of ketogenic diet and loss of control with introduction of carbs led us down this path.
o We sought to modify the process of glycolysis. 2DG interrupts one of the steps. A glycolytic inhibitor
o 2DG has been used as a tracer in Pet scans for decades
o Effective in 6PO and IP
o HZ models, also audiogenic sizures in Fring’s mice, and in status epilepticus induced by pilocarpine.
o Low effective doses: ED50 37.5 – 106 mg/kg
o Favorable preclinical tox profile. Through P1 in cancer.
o Slows progression of epilepsy by 2 fold in kindling models.
o New MOA
o Sz’s increase glycolysis; 2DG slows that progression.
o IP owned by Wharf, licensed to NeuroGenomix. Use patents.
o Devel Challenges
o Complete preclin and move to IND this year
o Challenge to design clin trials to take advantage of animal model suggested epilepsy.
o Probably focal epilepsy initial target but other ideas as well

Q&A

o Doses vs. Imaging
o Orders of magnitude higher.
o But small amount of white sugar, ½ a coke.
o Do believe safety profile a real advantage
o Our doses below those used in P1 cancer trials.
o Taken up preferentially in areas of seizue focus

NeuroGenomix

• Parkinsons moving p1 to p2 this year.
• Epilepsy NPY AAV primate study this year.
• Challenge of double requirement for regulatory approval because combined drug device

Q&A

1. Infusion
• 2 hour, outside of OR
• Single infusion

Asklepios Biopharmaceutical: ASKCNS109

• Small peptide Galanin
• Has been shown to attenuate szs in a number of animal models, overexpression induces sz activity
• Using AAV…stable gene deliver over 9 years shown, 4 years in a patient.
• Excellent safety profile (preclin and clin p2&3)
• Thomas McCown Nature Medicine Also Trneds in NeuoScience Review
• Biological Nanoparticle platform vector (BNP)
• Ip licensed by GSK, Meck, MDT and others
• Multiple POC and clin studies supports CNS delivery system.
• Valdiated in clinic:use in muscular dystrophy.
• Rodent models going on in epilepsy.
• Top level tox and primate ahead.
• Milestones and timelines:
o Epilepsy pre-clin initiation 11/07
• Dennis Spencer to do clinical study.
• IND anticipated in 2008
• TLE focus
• Single treatment

Q&A

• Regulating expression of Neuropeptide
o Good question, not doing yet
o We are testing regulated systems but not ready for prime time.
o That would be a second generation effort.

Marinus, Ganaxalone, Betsy Garafola
• Mike Rogawski and others expert on MOA, in development for a long time
• Licensed from Purdue pharma. Purdue and Co-Census had undertaken devel.
• A neuro-steroid without steroid issues.
• Initial trials in migrane. Negative. PK misunderstandings.
• Marinus has improved formulation. Lots of safety data in man though we are achieving higher concentrations.
• Open label trial in kids with infantile spasms in France.
• P2 trial in IS
• Adult partial seizure trial with n= 24. underpowered but good trend to efficacy and separation.
• We are in P2 for epilepsy. 2 trials wrapping up enrollment after one year this month.
• IS a cross-over design with cohorts. Well tolerated.
• Adults partial seizures more conventional baseline, double blind.
• Cohort of catamenial epilepsy part of P2 sub analysis.
• No reproductive issues in animals.
• Data in Q3/Q4. Then determine where we go in P3.
• May look to Infantile Spasms. Another company may gain approval first.
• Also potential via Gaba A in anxiety and other indications.

Q&A

• Exacerbation in absence epilepsy?
o Yes, true in animal models. Would not want to use there.
• Hypnotic effect?
o Looking at that issue in infants
 At therapeutic blood level, does not appear to be much in the way of sedative effect in animal models. Would be a concern if you pushed the levels. Did not see that in migraine studies and have not seen in our P2.

Vistagen, Ralph Snodgrass, AV-101 NMDA RA

• Orally available pro-drug
• Acive in neuropathic pain and sz models
• Potential in parkinson’s and Huntingtons
• Generates 7-cl-KYNA, a potent and slecive Glybsite antagonist.
• Enhance delivery to area of seizure focus.
• Favorable safety and metabolism profile
• IND to be filed end of April
• Have optimized manufacturing over last several years.
• 43% reduction in seizures in chronic limbic sz model
• Also active in Kainate induced seizures
• Not active in MES or GAERS
• Active in np pain.
• Next step: Ind next month. File as orphan drug.
• Find a partner.

Q&A

• How long will it last?
o Half-life in serum 3 hours of active compound.
• Concern about NMDA receptor antagonists exacerbating epilepsy from 1990’s studies and also serious side-effect issues?
o Note that the binding site for the NMDA ra is different for this…glycine site…20x more potent on the glycine site than kimeric acid?

Ovation, Stephen Collins
• Clobazam:
o LGS
o Now in P3
o Widely used in Europe, 1 mil patients
o Only 1,5 Benzo. All others 1,4.
o Acts thru Glutamergic and GABAergic mechanisms.
o Filed Orpan indic for lgs.
o Tolerance: 1 year, 7.5% vs. 4.2% and 6.7% Tegretol and Dilantin, better safety
o High dose: 85% reduction in drop sz’s vs 12% placebo.
o Non-drop: 45% reduction.
o P3 Q307- Q408. Q1 2009 Pre-NDA Mtg. Q2 NDA. 4Q ’09 action letter.
• IV Carbamazepine
o Challenge to create quick timeline to earn a return.
o Formulation patent ot 2025
o Replacement therapy for patients taking CBZ
o Moved directly into P3
o 78 enrolled, need 100, will file by year end.
• Sabril
o NDA accepted February.
o P2 in cocaine and meth abuse

Q&A

• Visual Field Defects
o 6 years to ?
o Good option if it works for you.
o If it does not work in 2-3 months, you can come off and reduce risk very significantly

Jazz Pharma, Jouko Isojari, MD PhD

• Palo Alto, CNS focused company
• 2 epilepsy compounds, one new nce, one reformulated.
• JZP-4
o Son of lamotrigine
o Inhibits sodium and calcium channels
o Activity in MES, PTZ, absence, partial and 6 Hz
o Also activity in depression, anxiety, and pain animal models
o Composition of matter and use patents
• Challenges
o Recruitement for clinical studies
o Will need to use locations outside the US and EU, challenge of gaining high quality data from those locations
• Submitted IND
• Once a day formulation developed.
• 2 human proof of concept studies
• H1 09 long term carcinogenicity studies
• Q3 08 first patient in epilepsy p2
• Target NDA submission in 2012.
• Efficacious with a broad spectrum of activity based on preclin and proof of principal studies.
• JZP-8: Intranasal Clonazepam for ARS (Acute Repetitive Seizures)
o Used for 30 years in IV form for emergency treatment of seizures in Europe.
o Limited acute options. Alternative to Diastat desired.
o Easy, socially acceptable delivery.
o Long half life of Clonazepam attractive.
o PK done in healthy volunteers. Get in fast, couple of minutes, t max in 12 minutes. Decent serum concentrations for several hours.
o Challenge: Recruitement in P2, P3.
o P2 in 20008. P3 to begin H1 2009.
o Target NDA in H1 2011

Q&A

• Human trials of JZP-4
o In 300 humans, no concerns yet.
• Clearance
o Don’t know
• FDA claim
o Add-on therapy

NeuroAdjuvants, Neuropeptides for epilepsy and pain, Steve White

• Galanin as proof of concept
• Developed with Greg Bulaj
• Anticonvulsant, antinociceptive
• Large size, does not cross the blood brain barrier.
• We have modified it to make it metabolically stable and allow it to cross the bbb.
• Orally available “to some extent”
• Inactive MES
• Activity in PTZ, 6 Hz, Frings audiogenic, corneal kindling, hippocampal kindling.
• Good protective index
• Active in 2 models of pain: Formalin mouse and rat and sciatic ligation rat.
• Development challenge: finalize SAR studies to id IND candidate for tox.
• Patents for composition of matter and use for epilepsy
• ERF funding and now R21.