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April 3,2019 Global Pharmaceuticals Primer on the Depression Market RESEARCH ANALYSTS Vamil Divan,MD(212)538-5394 vamil.divancredit- Uy Ear(212)325-1729 uy.earcredit- Inanc Caner(212)325-5051 inanc.canercredit- Michael V.Morabito,Ph.D.(212)-325-7298 michael.morabitocredit- European Pharma Team(44)-207-888-0304 creditsuisse.pharmateamcredit- DISCLOSURE APPENDIX AT THE BACK OF THIS REPORT CONTAINS IMPORTANT DISCLOSURES,ANALYST CERTIFICATIONS,LEGAL ENTITY DISCLOSURE AND THE STATUS OF NON-US ANALYSTS.US Disclosure:Credit Suisse does and seeks to do business with companies covered in its research reports.As a result,investors should be aware that the Firm may have a conflict of interest that could affect the objectivity of this report.Investors should consider this report as only a single factor in making their investment decision.Depression Still a Large Market,with Potential to Return to Growth:Depression remains a therapeutic area of significant investor interest given the large patient population(16.5MM adults and growing in the US alone)and the impact the market can have on multiple biopharma companies,with sales of$4Bn in 2018(coming mostly from generic products)and growing to$6Bn by 2026 based on our estimates.We are publishing a primer on the depression space with a look at current market trends and the latest novel drugs that look to disrupt the market.We will also discuss this various dynamics in this market during one of our expert panels at our 11th Annual Therapeutics Day this Friday,April 5.Please let us know if you need more information on this event.Novel Mechanisms Looking to Rejuvenate Genericized Market:Generic versions of older drugs with similar MOAs(e.g.,SSRIs,SNRIs,NDRIs)currently account for 80%of prescriptions in the anti-depression market.Delivering positive clinical data in depression trials remain notoriously challenging given unpredictable placebo response rates seen in these trials.However,we are seeing a renewed interest by biopharma companies to develop novel anti-depressants with different mechanisms to address what remains an area of significant unmet medical need and where there is a potentially large market opportunity.Spravato,Zulresso New Entrants Into Anti-Depressant Market:Both JNJs Spravato(esketamine)for treatment-resistant depression and SAGEs Zulresso(brexanolone)for post-partum depression are now FDA-approved and highlight the innovation we continue to see in the depression market.However,commercialization and reimbursement dynamics will be important to watch for both products given that their indications are for specific sub-segments of the broader depression population and unique features around how these drugs will be administered and how patients on these products will need to be monitored.Depression Drug Development Notoriously Risky,but Large Unmet Need Still Drawing Many Players:We have also seen some high-profile anti-depression pipeline assets fail their Phase 3 studies,most notably Alkermes ALKS-5461 and Allergans rapastinel.Several agents remain in development from various biopharma companies.We provide an overview of these products and where they stand in this note.2 Underlying Basis for Depression Still Not Well Understood,but Impact of the Disease Is Clear and Significant Depression is a chronic condition with an unknown cause,though chemical imbalances in the brain,genetics,and hormones are all thought to play large roles Major depressive disorder(MDD),commonly known as just“depression”,is defined as having experienced at least one two-week period of depressed mood in the past year There are different types of depression,including atypical,catatonic,postpartum,and seasonal affective disorder Cognitive Behavioral Therapy,sometimes in conjunction with antidepressant medication(s)are usual initial treatments Left untreated(and sometimes even if treated),damage to relationships,self-harm,and suicide can occur DSM-V Diagnostic Criteria for MDD Source:NIMH,Diagnostic and Statistic Manual of Mental Disorders(DSM),CS Estimates&Analysis 3 Source:IHME,Global Burden of Disease Depression a Leading Cause of Morbidity and Lowered Life Expectancy Worldwide Healthy Years Per 100k Inhabitants Lost Due to MDD(Morbidity or Mortality)Share of Countrys Population With Depression(2016)4 Antidepressant Market Is Large,but Also Crowded and Genericized 335 million scripts were written for antidepressants in the US in 2017 according to IQVIA Total TRxs grew on average 4%annually from 2013-2017 80%of the prescriptions come from generic products,highlighting the competition and pricing pressure in the market Out of the$4Bn in 2017 sales,$3Bn came from generic products Source:Company data,IQVIA(IMS),Credit Suisse estimates and analysis Note:IMS recently revised 2017 TRxs downward(from 335MM to 315MM);we use the unadjusted figures here and throughout to better represent the growth trend.050100150200250300350400450US TRxs(MM)5 Depression Continues to Be a Growing Problem Among US Adults Current agents often need to be taken for days to weeks before patients see a benefit,if they see a benefit at all Various side effects also limit how long patients are willing and able to stay on therapy About 30%of patients do not respond to treatment and are diagnosed with Treatment-Resistant Depression(TRD)Source:Company data,SAMHSA,Center for Behavioral Health,National Survey on Drug Use and Health,Credit Suisse estimates and analysis 16.517.610111213141516171820132014201520162017 2018E 2019E 2020E 2021E 2022E 2023E 2024E 2025E 2026EUS Prevalence of MDD in Adults,MM(2013A-2026E)Types of MDD Treatment Patients are Receiving(2017)Medication Only,6%Health Professional AND Medication,44%No Treatment,37%Health Professional Only,13%6 US Depression Market Has Supported Numerous Blockbusters in the Past,with Novel Agents Potentially Able to Reach These Levels as Well Source:Company data,IQVIA(IMS),Credit Suisse estimates and analysis The large number of patients along with relatively frequent switching between therapies makes the depression market an attractive one from a commercial perspective,especially for drugs with novel mechanisms of action Novel MOA drugs represent a multibillion dollar sales opportunity that multiple companies may divide up over the next decade even if the market doesnt grow,we see potential for adjunct use We currently model sales of approximately$6Bn for the US depression market in 2026 02,0004,0006,0008,00010,00012,000US Total Sales($,MM)7 Many Key Marketed Depression Drugs Have Similar Mechanisms Sources:Company data,Credit Suisse estimates Drug (Brand Name)ClassTherapeutic Dose Range(daily)Initial Suggested DoseTitrationPotential DifferentiationPotential DrawbacksBupropion (Wellbutrin SR)Norepinephirine and Dopamine Reuptake Inhibitor(NDRI)300 to 400mg150mgIncrease to 200mg if poor response,allow 8 hours before redosingStimulation,little or no sexual dysfunctionMay induce seizures in persons with seizure disorderCitalopram HBr (Celexa)Selective Serotonin Reuptake Inhibitor(SSRI)20 to 40mg20mgIncrease by 10mg every 7 days if no response after 4 weeksAnxiety relief,fewer cytochrom P450 interactionsHigher risk of arrythmia compared to other SSRIsDespiramine (Norpramin,Pertofrane)Norepinephrine Reputake Inhibitor100 to 300mg50mgIncrease by 25 to 50mg 7 days to initial target of 150mg in 4 weeksMore effect on norepinephrine than serotoninAnticholinergicEscitalopram Oxalate(Lexapro)Selective Serotonin Reuptake Inhibitor(SSRI)10 to 20mg10mgIncrease to 20mg if only partial response after 4 weeks10mg dose usually effective for most,not associated with weight gainHigher risk of irregular heartbeat,brain zaps,restlessnessFluoxetine HCL (Prozac)Selective Serotonin Reuptake Inhibitor(SSRI)10 to 80mg20mgIncrease by 10mg every 7 days if no response after 4 weeksAnxiety relief,long half-life,less frequent discontinuation symptomsToo much stimulation,cytochrome P450 interactions,long onsetMirtazapine (Remeron)Serotonin and Norepinephrine Antagonist15 to 45mg15mgIncrease in 15mg increments,maintain 30mg for 4 weeks before further increaseFew drug interactions,little sexual dysfunctionSedation at low dose only,may stimulate appetiteNortriptyline (Aventyl,Pamelor)Norepinephrine Reuptake Inhibitor25 to 150mg25mgIncrease 10 to 25mg every 5 days to 75mgLower orthostatic hypotension than other tricyclicsCan exacerbate cardiac conduction problemsParoxetine (Paxil)Selective Serotonin Reuptake Inhibitor(SSRI)10 to 50mg20mgIncrease by 10mg every 7 days if no response after 4 weeksFDA-approved for many other disordersSedationParoxetine CR (Paxil CR)Selective Serotonin Reuptake Inhibitor(SSRI)25 to 62.5mg25mgIncrease by 12.5mg every 7 days if no response after 4 weeksLess nausea and GI distressOccasionally more anticholinergic-like effectsSertraline (Zoloft)Selective Serotonin Reuptake Inhibitor(SSRI)25 to 200mg50mgIncrease by 25 to 50mg every 7 days if no response after 4 weeks,maintain at 100mg for 4 weeks before next increaseFDA-approved for anxiety,safe for patients who have previously had a heart attackHigher rate of psychiatric side effects and diarrhea compared to other SSRIsVenlafaxine,Venlafaxine ER(Effexor,Effexor XR)Selective Norepinephrine Reuptake Inhibitor(SSRI)75 to 375mg75mg37.5mg for one week,then 75mg for two weeks,then 150mg.If partial response after 4 weeks,increase to 225mgHelps anxiety,possibly fewer cytochrome P450May increase blood pressure at higher doses,expensive8 SSRI/SNRIs Is the Mainstay of Antidepressant Therapy Given the potential efficacy and relatively limited side effects(along with low cost),patients generally start therapy on a generic version of an SSRI/SNRI Nearly 70%of US anti-depressant prescriptions in 2017 were written for SSRI/SNRIs It is very common for patients to cycle between two or three different SSRI/SNRIs as they try to find the one that works best for them Over time many patients will progress to antipsychotics or electroconvulsive therapy,but these are more complicated to administer and tend to have more side effects Source:Company data,IQVIA(IMS),Credit Suisse estimates and analysis SSRI/SNRI,68%Wellbutrin+generics,11%Others,22%9 Fluctuating Severity and Response of Patients Over Time Can Make Treatment Difficult and Change the Optimal Course of Action Source:Company data,SAMHSA,Credit Suisse estimates and analysis 10 Therefore,a Significant Unmet Need Remains in Treating Depression Current agents often need to be taken for days to weeks before patients see a benefit,if they see a benefit at all Various side effects limit how long patients are willing and able to stay on therapy About 30%of patients do not respond to treatment and are diagnosed with Treatment-Resistant Depression(TRD)The recent approval of JNJs Spravato(esketamine)may help address that need Several drugs with novel mechanisms of action(MOA)are being evaluated and could also be approved for TRD in the coming years Source:Company data,SAMHSA,Center for Behavioral Health,National Survey on Drug Use and Health(2015-2016),Credit Suisse estimates and analysis Note:Numbers from ALKS Company Presentation 11 Multiple New Chemical Entities in Development for Depression,but Successful Development Has Proven to Still Be a Challenge(1/2)Sources:Company data,clinicaltrials.gov,BioMedTracker,EvaluatePharma,Credit Suisse estimates CompanyDrugIndicationClassMechanism of Action Potential DifferentiationPotential DrawbacksCurrent Dev.Stage (for MDD/TRD,unless otherwise stated)Estimated Launch DateConsensus WW Sales(2024)J&JSpravato(esketamine)Treatment-Resistant Depression(TRD);to be used alongside oral antidepressantNMDA receptor antagonistPotentially increases dopamine and has dissociative properties,may lead to euphoriaNasal spray with rapid onset,may help decrease suicidal ideation,adjunctive with oral antidepressantPotential for addiction,potential for cognitive impairmentApproved Mar 4 2019 Mar 2019$1.6BnSageZulresso(brexanolone)Postpartum Depression(PPD)Positive allosteric modulator of GABA-A receptorUnknown,thought to regulate function to desirable levels instead of complete activation or inhibition of the GABA-A receptorRapid onset,possible remission of symptoms after 60 hours,potentially first approved treatment for PPD,non-narcotic steroidMust be infused intravenously every 12 hours for 60 hours,possible sedation,possible buildup of tolerance if a second infusion would be needed at a later timeApproved Mar 19 2019Jun 2019$370MMSageSAGE-217(brexanolone)Major Depressive Disorder (MDD);Bipolar Disorder;Insomnia;Parkinsons DiseasePositive allosteric modulator of GABA-A receptorUnknown,thought to regulate function to desirable levels instead of complete activation or inhibition of the GABA-A receptorOral,once daily,rapid onset,episodic,possible remission of symptoms after two weeks,non-narcotic steroidPossible sedation and/or upper respiratory tract infection;possible buildup of tolerance over timePositive Phase 3 PPD Data Jan 2019,Phase 3 MDD Results in 4Q19/1Q20 2021$2.2BnMinerva/J&Jseltorexant(MIN-202)aMDD;InsomniaSelective orexin2 antagoinstBlocks activiation of neurons in brain that promote wakefulness by binding to orexin-2 receptorsMay counteract insomnia and improve sleep quality,especially in people with high cortisol levelsPossible sedation2 Phase IIb aMDD Studies;Topline Mar/Apr 2019 and 2Q19,respectively.Insomnia Topline 2Q192021N/AMinervaMIN-117MDD+Anxiety (as monotherapy)Effect thought to be largely mediated by serotonin and dopamine;preventing reuptake5-HT1A blocker;5HT transporter;Alpha1-a,b modulator;Dopamine transporter;5-HT2A antagonistRapid onset,bolsters serotonin and dopamine concentrationPossible safety+tolerability concerns by some doctorsPhase IIb Topline Results in 2Q192021N/ANote:Selected drugs have at least one targeted indication of MDD/its subtypes,and are also currently in Phase II or beyond(according to clinicaltrials.gov)12 Multiple New Chemical Entities in Development for Depression,but Successful Development Has Proven to Still Be a Challenge(2/2)Sources:Company data,clinicaltrials.gov,BioMedTracker,EvaluatePharma,Credit Suisse estimates CompanyDrugIndicationClassMechanism of ActionPotential DifferentiationPotential DrawbacksCurrent Dev.Stage (for MDD/TRD,unless otherwise stated)Estimated Launch DateConsensus WW Sales(2024)VTGNL-4-chlorokyurenine(AV-101)aMDD,MDD,neuropathic pain,PD L-DOPA-Induced Dyskinesia,Suicidal Ideation,Epilepsy,Huntingtons DiseaseNMDA receptor antagonistModulates dopamine and GABA transmission after metabolizationNear-instant onset,found to be neuroprotective in animal modelsCompletely inactive until ingested and metabolizedaMDD Phase II trial to readout in 2H19;MDD Phase II trial to readout 1H202022N/AAxsomebupropion+dextromethorphan (AXS-05)TRD,agitation in Alzheimers,smoking cessation,MDD NDRI,nAChR antagonist+SNRI,Sigma-1 agonist,NMDA antagonistoral NMDA receptor antagonist with multimodal activity;Buproprion interferes with rapid DXM met