Combination Therapies: the promise to cure… everything??

By I&C President Ryan WittBy I&C President Ryan Witt

witt.rj@gmail.comwitt.rj@gmail.com

Cure everything???!?Cure everything???!?

CancerCancer Cardiovascular Cardiovascular

diseasedisease Alzheimer’s DiseaseAlzheimer’s Disease Bacterial InfectionsBacterial Infections

Yes. I’ll Explain.Yes. I’ll Explain.

ALSALS Multiple SclerosisMultiple Sclerosis HIV/AIDSHIV/AIDS HepatitisHepatitis

But, RememberBut, Remember

Ask Ask QQs!s!

AlwaysAlways ask “How, Why, What, and ask “How, Why, What, and When”When”

Try to Understand EVERYTHING!Try to Understand EVERYTHING!

ConceptConcept

With a With a knowledgeknowledge-based approach, -based approach, what can we do?what can we do?

Knowledge we needKnowledge we need Nearly every drug approved on the market, by a regulatory

agency, has a known molecular mode of action. If you distinguish the molecular characteristics of a disease

from a “normal” cell’s characteristics, you can then match drugs with that disease and known molecular signaling pathways within a disease!

This is the idea fueling (i) “Combination Therapies” and (ii) “Drug Repositioning”

CurrentCurrent Treatment (Rx) and Drug Treatment (Rx) and Drug Development Protocols for Development Protocols for

DiseasesDiseases Past: Age of Past: Age of One Drug WondersOne Drug Wonders

Penicillin – bacteriaPenicillin – bacteria

Now we face tougher problems… Now we face tougher problems… 1.1. Multigenetic diseasesMultigenetic diseases – cancer, Alzheimer’s and – cancer, Alzheimer’s and

Parkinson’s diseases, cardiovascular disease, Parkinson’s diseases, cardiovascular disease, MS, HIV / viruses…MS, HIV / viruses…

2.2. Disease ResistanceDisease Resistance Infectious DiseasesInfectious Diseases HIVHIV CancerCancer

Disease Complexity / Disease Complexity / MultigeneityMultigeneity

Cancer has been called hundreds of sub-diseases; reason is Cancer has been called hundreds of sub-diseases; reason is because it results from multiple diff’t molecular because it results from multiple diff’t molecular dysfunctions.dysfunctions.

Molecular Signaling within cells is highly complex.Molecular Signaling within cells is highly complex.

Disease ResistanceDisease Resistance

Arises fromArises from1.1. Not fully killing the diseased cells and/orNot fully killing the diseased cells and/or

2.2. Some degree of adaptive “randomness” in the Some degree of adaptive “randomness” in the disease; anddisease; and

3.3. ““Selection” to grow those diseased cells who Selection” to grow those diseased cells who were not killed or are more adept.were not killed or are more adept.

With Cancer and HIV: the molecular systems driving these diseases are constantly changing due to high mutation and growth rates. (they adapt!)

Resistance Development Resistance Development withinwithin

One CellOne Cell

““Window of Opportunity” with diseases where you can Window of Opportunity” with diseases where you can strike based on armaments available, and strike HARD!strike based on armaments available, and strike HARD!

PARP up-regulated after chemotherapy, if missing DNA PARP up-regulated after chemotherapy, if missing DNA repair enzymes of BRCA and PTEN family.repair enzymes of BRCA and PTEN family.

As you see later, cocktail As you see later, cocktail couldcould be better! be better!

Cancer upregulates PARP (another DNA repairman), thus defending itself against too much DNA damage.

Cancer w.dysfunctional PTEN

Chemo

Chemo mutates DNA of cells to kill them!

Cancer w.dysfunctional PTEN

PARP-1

What is a combination What is a combination therapy?therapy?

The combination of two or more separate The combination of two or more separate components – be it drugs, medical devices, or components – be it drugs, medical devices, or biological products (a substance derived from a biological products (a substance derived from a living organism), for the purpose of some end-living organism), for the purpose of some end-goal.goal.

GoalGoal

a)a) Big attack – not in size but strengthBig attack – not in size but strength

b)b) Localized attackLocalized attack

ConceptConcept It’s better to fight something with two or more It’s better to fight something with two or more

small attacks specific (molecularly) to a target, small attacks specific (molecularly) to a target, both in effectiveness both in effectiveness andand safety, when compared safety, when compared to one single massive attack.to one single massive attack.

i.e., Nuke v.i.e., Nuke v. Targeted Targeted AssassinationsAssassinations

Support from Studies (all entering or in clinical Support from Studies (all entering or in clinical validation testing now):validation testing now):

1.1. Cocktail against brain tumorsCocktail against brain tumors2.2. MET / EGFR cocktail – more on this laterMET / EGFR cocktail – more on this later3.3. Chemo targeted to liver, avoiding adverse effects to heartChemo targeted to liver, avoiding adverse effects to heart4.4. HIV Cocktail – Atripla (*approved)HIV Cocktail – Atripla (*approved)5.5. Cocktail against Alzheimer’s Disease Cocktail against Alzheimer’s Disease

The BenefitsThe Benefits

1.1. Greater effectiveness on disease targetGreater effectiveness on disease target

2.2. Lower side effects on host (me and you)Lower side effects on host (me and you)

3.3. Lower chance of resistance development (from Lower chance of resistance development (from disease)disease)

TheoreticalTheoretical Examples: Examples:applying the conceptapplying the concept

CancerCancer

Other studies where relevance is shownOther studies where relevance is shown MSMS ALSALS Alzheimer’sAlzheimer’s Parkinson’sParkinson’s

HIVHIV Infectious diseases Infectious diseases

(viruses/bacteria)(viruses/bacteria) Hepatitis B recurrent in post Hepatitis B recurrent in post

liver transplant & Hepatitis Cliver transplant & Hepatitis C

CancerCancer

EGFREGFR & & METMET therapy (on its way to clinical studies now) therapy (on its way to clinical studies now) FUS1FUS1, , MDM2MDM2, & , & P53P53 therapy (tested separately in clinical therapy (tested separately in clinical

trial)trial) PARP + Chemo – breast and ovarian cancer (in clinical PARP + Chemo – breast and ovarian cancer (in clinical

trail now)trail now) Brain Tumors – 3 proteins targeted (on its way to clinical Brain Tumors – 3 proteins targeted (on its way to clinical

studies)studies)

EGFR & METEGFR & MET

““Our findings provide a strong rationale for combination Our findings provide a strong rationale for combination treatment strategies as initial therapies for some patients.” - Pasi treatment strategies as initial therapies for some patients.” - Pasi Jänne Jänne MD, PhD, of Dana-Faber Cancer Institute and Associate Professor MD, PhD, of Dana-Faber Cancer Institute and Associate Professor of Medicine at Harvard Medical Schoolof Medicine at Harvard Medical School

Status: expected to move into clinical study soonStatus: expected to move into clinical study soon

Source: http://www.medicalnewstoday.com/articles/176486.php?nfid=79262

EGFRi

Tarceva / Iressa

HGF

cancer

cancer

cancer GAB1++

cancer

cancer

cancer

cancer

cancer

MET

EGFR

METi

Tumor Response

FUS1FUS1, , MDM2MDM2, & , & P53P53 therapytherapy

Tested in clinical trials separately.

PARP inhibitors & PARP inhibitors & ChemoChemo

Being tested in clinical trial now, with “very Being tested in clinical trial now, with “very promising results.” – Medscape articlepromising results.” – Medscape article

PTEN + BRCA 1/2 + PARP = DNA Repairmen

When no PTEN (or BRCA1/2), PARP is active/over-expressed, especially in cancers after undergoing chemotherapy.

Idea for Cancer Therapy is giving PARP inhibitors to people who have already undergone chemotherapy to prevent this defense mechanism OR PARP inhibitors, with chemo, as a first line treatment.

This makes sense b/c cancer cells don’t want to be mutated and die from the chemotherapy, thus defend themselves through upregulating PARPs (repairmen) when they don’t have PTEN or BRCA proteins.

Sources: http://www.medscape.com/viewarticle/704990; http://news.bbc.co.uk/2/hi/health/8256494.stm; http://breastcancer.about.com/od/targetedbiologictherapies/p/parp_basics.htm

Brain tumorsBrain tumors

1.1. Interleukin 13 receptor alpha 2 (IL-13R-alpha),Interleukin 13 receptor alpha 2 (IL-13R-alpha),2.2. Ephrin receptor A2 (EphA2)Ephrin receptor A2 (EphA2)3.3. Fos-related antigen 1 (Fra-1)Fos-related antigen 1 (Fra-1)Among 76 patients with brain tumors, all with Among 76 patients with brain tumors, all with

GBMs had one marker present and 95% had at GBMs had one marker present and 95% had at least two of these markers.least two of these markers.

““The three markers were not found in healthy brain The three markers were not found in healthy brain tissue, suggesting that the proteins are highly tissue, suggesting that the proteins are highly suited as targets for therapies designed to kill suited as targets for therapies designed to kill cancer cells and spare healthy brain tissue.”cancer cells and spare healthy brain tissue.”

Source: http://www.drugresearcher.com/Emerging-targets/A-drug-cocktail-to-bust-brain-tumours

A few quotesA few quotes ““This is why it's so important to be able to use a combination of This is why it's so important to be able to use a combination of

more than one drug. If the virus mutates tomore than one drug. If the virus mutates to become resistant to become resistant to one drug, it is still sensitive to the other drugsone drug, it is still sensitive to the other drugs.”.”

-- Genhong Cheng, Genhong Cheng, Research team member at the UCLA Center for Cell Research team member at the UCLA Center for Cell Control and UCLA's Jonsson Comprehensive Cancer CenterControl and UCLA's Jonsson Comprehensive Cancer Center

““Drug combinations can also be used effectively to inhibit Drug combinations can also be used effectively to inhibit infectious diseases because resistance to a single drug is very infectious diseases because resistance to a single drug is very common… If we can apply multiple drugs against one infectious common… If we can apply multiple drugs against one infectious agent, it probably will prevent the occurrence of drug agent, it probably will prevent the occurrence of drug resistance.”resistance.”

- Ren Sun, Ren Sun, UCLA Professor of Molecular and Medical Pharmacology and UCLA Professor of Molecular and Medical Pharmacology and research team memberresearch team member

From a study finding that total inhibition of a virus occurred at From a study finding that total inhibition of a virus occurred at much lower drug doses than would be necessary if the drugs much lower drug doses than would be necessary if the drugs were used alone (~10% less than required when each drug is were used alone (~10% less than required when each drug is adminstered individually)adminstered individually)

But, rememberBut, remember

AlwaysAlways ask: Why, How, What, and ask: Why, How, What, and WHENWHEN

Any Questions?Any Questions?

Ex of Cocktails ApprovedEx of Cocktails Approved

Only one approved cocktail comes to Only one approved cocktail comes to mind –mind –

1.1. HIV, there is now one “cocktail” pill you HIV, there is now one “cocktail” pill you can take which includes all three primary can take which includes all three primary therapies for the disease.therapies for the disease.

Approved post approval of each individual Approved post approval of each individual component.component.

2.2. Combo, chemotherapies + monoclonal Combo, chemotherapies + monoclonal Antibodies like Herceptin / EGFR targetsAntibodies like Herceptin / EGFR targets

Approved after testing one experimental therapy Approved after testing one experimental therapy in combo with already approved chemo drugs.in combo with already approved chemo drugs.

WhenWhen

WhenWhen matters! matters!

If you don’t get why after these next few If you don’t get why after these next few slides, stop me in my tracks!!slides, stop me in my tracks!!

Importance of Timing in the Importance of Timing in the Development of Combo-Development of Combo-

TherapiesTherapiesPhysician Developed

1.1. Two or more approved therapiesTwo or more approved therapies Dosage and interactions are untested!Dosage and interactions are untested! Possibly can try to predict dosage/interactionsPossibly can try to predict dosage/interactions

Pharma Development by testingPharma Development by testing

2.2. An approved therapy with (i) an investigational or (ii) An approved therapy with (i) an investigational or (ii) another approved therapyanother approved therapy

Avg time for development – Avg time for development – 14 years14 years for a cancer for a cancer therapy!therapy!

Many pharmas know now of possible combo benefits, but test each drug one at a time anyway..

3.3. Combo of two investigational therapiesCombo of two investigational therapies Never happened to my knowledgeNever happened to my knowledge

Problems with Physician Problems with Physician Developed CombinationsDeveloped Combinations

Each individual component is tested for max Each individual component is tested for max tolerable dose…tolerable dose… Hence, when combining two or more drugs, Hence, when combining two or more drugs,

physicians have no idea what dose to give physicians have no idea what dose to give patientspatients

Also: potential interactions between drugs are Also: potential interactions between drugs are unknown.unknown.

Innovation in the WorksInnovation in the Works The development of cocktails The development of cocktails from pharmasfrom pharmas

(where dosage and safety are tested prior to (where dosage and safety are tested prior to administration to patients)administration to patients)

Drug repositioningDrug repositioning

But, for nowBut, for now

Combination Rxs Used NowCombination Rxs Used Now

Combination therapies are primarily created by Combination therapies are primarily created by physicians through “off-label use” or already physicians through “off-label use” or already approved chemotherapy-combo regimens.approved chemotherapy-combo regimens.

What to do?What to do?

Ask your physician about being Ask your physician about being treated with a potent, specific treated with a potent, specific regimen–targeted to regimen–targeted to youryour disease– disease–especially, if you are dealing with a especially, if you are dealing with a seriously compromising illness.seriously compromising illness.

Ask your doc Qs:Ask your doc Qs: “How, what, why, “How, what, why, and when?”and when?”

What is I&C Doing?What is I&C Doing?

Bringing innovation to you at the Bringing innovation to you at the fastest rate possiblefastest rate possible is our goal. is our goal.

1.1. Community-based education and resource Community-based education and resource sharingsharing

2.2. Building an interface to empower you to make Building an interface to empower you to make a difference a difference

3.3. Working to integrate these innovations and Working to integrate these innovations and patient options into physicians’ workflow.patient options into physicians’ workflow.

Combination Therapy Combination Therapy ResourcesResources

Targeted Drug Delivery ToolTargeted Drug Delivery Tool IsoFlowIsoFlow Ultrasound released therapy (untested in Ultrasound released therapy (untested in

humans)humans) UV activated therapy (untested in humans)UV activated therapy (untested in humans)

Drug repositioning / finding for your diseaseDrug repositioning / finding for your disease GeneGoGeneGo – – MetacoreMetacore BiovistaBiovista

Targeted approach specifically for cancer– Targeted approach specifically for cancer– N-of-OneN-of-One Intervention InsightsIntervention Insights / / GeneGoGeneGo ICANICAN