1、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 awar
2、e 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.25 August 2019Americas/United StatesEquity ResearchBiotechnology U.S.Biotechnology COMMENTResearch Analys
3、tsMartin Auster,M.D.212 325 6573martin.austercredit-Tiago Fauth212 325 7569tiago.fauthcredit-Mark Connolly212 325 7576mark.connollycredit-Biotech Bus Tour Investor Meeting NotesWe hosted a Boston Bus Tour last week.Here are our complete notes from our meetings with companies under coverage(in the or
4、der seen):RARX,XLRN,ALXN,ARNA,RARE,and SRPT.RARX CS Overview:RARX is building an interesting and(for now)differentiated pipeline for its anti-C5 peptide recently adding the IMNM indication and a 3rd Neuro indication expected to be announced within the next month to complement its Ph3 gMG program for
5、 zilucoplan.XLRN CS Overview:We called XLRN a sleeper idea in our H219 preview and continue to think investors may be overlooking a nice balance of what we see as fairly high probability catalysts-(1)luspatercept myelofibrosis update at ASH this Dec.that supports a move to Ph3.;and(2)luspatercept ap
6、provals in Bthal(Dec.2019)and MDS(Apr.2020)with a couple pipeline shots on goal with decent optionality and low investor expectation(suggesting limited downside risk).We see the sotatercept PULSAR data in early 2020 carrying a favorable skew,in particular.ALXN CS Overview:Management continues to exe
7、cute on its business plan,strengthening the base value of the business,while the stock price has tread water.We think the upcoming EU patent hearing and possible IPR issuance risks are mostly reflected in the current valuation and see a relief rally post-these events as the market refocuses on solid
8、 NT revenue and earnings momentum particularly in the Soliris CNS launches(gMG and,now,NMOSD)and Soliris to Ultomiris conversion.ALXN has completed 8 BD deals in past 18 months and will have 10 Ph3 trials running across its pipeline in 2020(about half are Ultomiris trials).ARNA CS Overview:Arena has
9、 a strong capital position($1.2b at Q2 2019),a potential multi-billion dollar revenue opportunity with Ph3 etrasimod in IBD,a substantial royalty potential with ralinepag and a couple lower-visibility,high optionality pipeline opportunities(etrasimod in AD and oloranib in IBS).Not a lot of major dat
10、a events in next 12 months,but a highly attractive valuation relative to commercial potential and clinical stage of its pipeline.RARE CS Overview:Crysvita commercialization has been strong and on track with expectations.RAREs pipeline is among the most robust for companies this size,offering investo
11、rs an opportunity to invest in a company that harnesses multiple modalities(gene therapy,oligonucleotides,traditional therapeutics).Near-term,management sounds optimistic that its two gene therapy updates expected within the next month(OTC deficiency and GSD1a)may support advancement of these prospe
12、cts to Phase 3;we expect these updates to set the tone for shares over the balance of 2019.25 August 2019U.S.Biotechnology2SRPT CS Overview:The bus tour discussion heavily focused on details of the recent golodirsen CRL,which has caused considerable share volatility in the past week.We continue to v
13、iew this companys value as being driven by success(or lack thereof)in its gene therapy pipeline in DMD,LGMD,and beyond.We do not see incremental regulatory risk associated with SRP-9001 owing to last weeks events(SRP-9001 Ph3 is a pbo-controlled study with a functional primary endpoint,which we beli
14、eve provides an incontrovertible efficacy argument from which to evaluate the assets risk-benefit).Regulatory updates on golodirsen/casimersen and on SRP-9001s Ph3 protocol alignment with FDA are expected before YE 2019.25 August 2019U.S.Biotechnology3Ra Pharma(RARX)CS OVERVIEW:RARX is building an i
15、nteresting and(for now)differentiated pipeline for its anti-C5 peptide recently adding the IMNM indication with a 3rd Neuro indication expected to be announced within the next month to complement its Ph3 gMG program for zilucoplan.Introduction PR this morning announced Ra earned development mileston
16、e from partner Merck as a result of dosing first patient in a Ph1 trial evaluating orally-available macrocyclic peptide(discovered by Ra)This is the second peptide from the platform to enter clinic;highlights companys strong technology.Zilucoplan:C5 inhibitor;can do whatever a mAb does.Finished Ph2
17、gMG study,has had regulatory interactions across the globe(US/EU/JP).Will start gMG ph3 H2 of the year.Zilucoplan has been dosed for over 2 years,with excellent compliance and tolerabilityAnnounced second indication in the neuromuscular space IMNM Attractive indication as follow-on Autoimmune diseas
18、e,know it is caused by auto antibodies;patients treated with a similar regimen to gMG(steroids,immunosuppressive agents,IVIg/PLEX)Complement activation has been characterized in the indicationOther companies are struggling to make SC formulations for mAbs C5 inhibitors;thinks Ra is well positioned i
19、n the space.Will announce a third neuromuscular indication within the next month or so Unlike IMNM,people will be very familiar with this indicationCompleted ethno-bridging study,supporting no need for dose modification.Can quickly go into JP clinical trialExtended release formulation 2 products PoC
20、 for weekly delivery in monkey.Stable and complete suppression of complement for a week with a standard PLGA technology(several drugs on the market).Separately,announced collaboration with Camurus in July 2019.FluidCrystal-injects a liquid that forms a depot under the skin,and the company believes i
21、t can have a potentially weekly delivery with that formulation No technical issue for a weekly formulation,its a matter of safety/tolerability,and will have a better idea once gets into clinic Pk/Pd healthies to start H1 2020Company has$300m in cash,which is expect to fund operations at least throug
22、h the end of 2021 Q:Several MG studies ongoing,can this market accommodate all these studies?What are enrollment headwinds?Why confident zilucoplan could be one of several agents and still capture share?From Ph2 experience,trial enrolled faster than predicted and overenrolled25 August 2019U.S.Biotec
23、hnology4 Reflection of interest from physicians/patients on getting in a complement inhibitor,even with Soliris on the market.Unclear whether FcRn has the same efficacy versus complement.Clearly positive trials with C5 inhibition.FcRn has had only 2 trials-one looks positive(but with imbalance at ba
24、seline),the other showed similar Pd but not the same benefits,so a lot of doubts on the FcRn space.For the Ph3,we are offering a once-daily,5-8 sec injection,dosed at home,no port,no trip to hospital,12-week treatment duration,no requirement of patient failing prior therapies.Other studies enrolling
25、 have up to a 6 month placebo period.For patients,that want to receive drug,the 12-week period prior to crossing to drug if they are randomized to placebo is appealing.Received interest from many sites.All Ph2 sites will be involved in the Ph3 The Ph2 had around 30 centers;this trial will have about
26、 80 centers.Ph2 only US;Ph3 also has centers in JP/EU.While other trials are going on,RARX hasnt had an issue bringing sites on board.Company sees big opportunity;MG is rare,but it is still a substantial market;more patients than hemophilia,for example.Q:How may zilucoplan fit within the treatment p
27、aradigm?Regardless of treatments available,some pts still dont respond.They still need help.Want to offer a convenient,prefilled syringe,at room temperature Believes can offer an attractive price point;has alluded to a price point of around$300k(half of Soliris)Believes complement is a potentially b
28、etter approach in gMG 3 clearly successful studies(Soliris Ph2 and Ph3,zilucoplan Ph2).Patients in RARXs study were just as sick and felt just as bad as the REGAIN(Soliris)study,just werent required to have failed multiple prior IST.Soliris is a$700k product with a$1b run rate marketed to only 10%or
29、 so patients.Those same pts,and a larger proportion that havent failed multiple prior therapies,can go in our therapy at a price point that is significantly lower.Q:Profitability of a cyclic peptide?Synthetic product,a lot of advantages in manufacturing and shipping(room temperature).Company thinks
30、it will have attractive COGS%at this price range.Q:Do you expect competition from other complement inhibitors in MG over time?Dont think C3/factor D will go into gMG.C3 involved,but not to the same extend as PNH or aHUS;same for factor D.C5 is likely the safest bet.There will be people that may not
31、mind a large volume delivery,or a trip to hospital(as required with Soliris/Ultomiris).SC delivery of anti-C5 mabs is still challenging.25 August 2019U.S.Biotechnology5Think we will always have the complete orthogonal product-small volume,small syringe,accessible product.As Alexion moves patients to
32、 Ultomiris,will take the shine away from biosimilars.Think this market will largely be RARX and ALXN.Peptides are 40-50 x smaller than mabs.We have done some work showing potential for better tissue penetration(CNS,muscular junction,etc.).If you contemplate giving IVIg,the physician cant co-administ
33、er a monoclona-will flush out the other therapeutic wont get the benefit of the two pathways,allows ziluoplan to differentiate from C5 antibodies.Q:Any risks for a peptide vs an antibody?Relative to small molecules,peptides are bigger,more points of contact,and generally fewer AEs.Think they are de-
34、risked.Beyond zilucoplan,Merck has also de-risked its peptide.Merck increased dosing,and the only“tox”observed was the on-target effect.Peptides are not that immunogenic relative to mAbs;they are very specific,which lowers off target toxicity.Not worried about anything;has 9 month preclinical data i
35、n monkeys with high doses,and no safety signal.Also conducted postnatal development studies(no impact in neonates,mother,and fetuses).Have a good package of preclinical toxicity going into an NDA.Q:Can you provide more details on the two technologies being developed for weekly delivery?PLGA,utilized
36、 by several companies,and several products.Challenge with C5 is that there is a lot,thats why Soliris doses are high.Small peptide can do the same thing with a smaller mass;pretty simple.Worked hard to load up the beads to get levels to where they want.Inject a solid micro-particle,with some manufac
37、turing challenges that have been solved several times in the past;needs to start with a sterile product,and come out sterile(one of the challenges).FluidCrystal is a liquid,many advantages in manufacturing.Can use filtration at the end of the process.PLGA requires some special equipment vs FluidCrys
38、tal that has a more simple process.Both allow for weekly administration.There is a lot of commercial experience with PLGA;there is less experience with fluid crystals(but on market for a year with a drug in EU).Importantly,zilucoplan is delivered completely unchanged with these technologies.Q:Volume
39、 of depot injection?Larger than daily,but think can get down to 1.5ml,no more than 2ml.25 August 2019U.S.Biotechnology6People using on body devices for a lot of products,Ultomiris is a 7ml SC infusion with two on-body patch pumps.Even without a weekly,the daily SC fits persons daily routines fairly
40、well.Q:Can you remind us of the IP position of zilucoplan?Have several issued that cover zilucoplan,issued in the last year or so.Thinks gives protection until 2036,and filed all over the world.Already have issued IP on zilucoplan(thats the CoM patent).Q:Why is$200-$300k the right pricing for the gM
41、G market?Feel that range is sweet spot.Its half of Soliris,but has the premium associated with our product profile.More importantly,compare it to IVIG/PLEX Chronic IVIG/PLEX is$150k+a year,but zilucoplan has additional benefits on convenience,safety,and at home administration.Range was well received
42、 by payers.Q:What is the patient mix in gMG?70%commercial,30%government.Age range tends to be younger females,or older males.Medicare exposure is moderate.Q:Can you give more details on the 3rd indication for zilucoplan?Dont want to say much about it right now.There is a fair amount of data showing
43、complement deposit in tissue,reasonable to assume causing pathology.Bigger than IMNM,smaller than MG,good size,and big unmet need.In the true neuro space;thinks peptides may have better diffusion Q:For the IMNM Ph2,what%CK reduction is meaningful?Start up for Ph2 going well,lot of interest.First pro
44、perly controlled trial in IMNM,not a lot of randomized trials.Know CK is a good biomarker in this indication Among adults with inflammatory myopathy-highest baseline CK Baseline CK is 7-10k,so very high CK level/drop shown to correlate with functional improvement.Responders with IVIg have seen rough
45、ly a 50%reduction in CK on average Confident a 50%or more drop in CK will be clinically meaningful.Will see impact early in the biomarker,but may take a little longer for functional endpoints(functional improvements may lag CK drops).Company would like to see 50%+CK reduction.If its complement media
46、ted,this should occurLiterature suggests IMNM is complement mediated 25 August 2019U.S.Biotechnology7 Q:How reliable is CK as an endpoint?Will you do any biopsies?Very clear the DMD case(high variability in CK improvements and consistency of reduced CK)doesnt apply for IMNM.These huge swings in CK d
47、o not seem to occur at all in IMNM according to physicians.The IMNM trial is not requiring biopsies.Have CK and other biomarkers of tissue damage Ph2 results will have 4 biomarkers measuring the“same thing”Company has a high degree of confidence it will be a strong signal.Biopsies not mandatory in t
48、he protocol,but physicians could take them.If were to do serial biopsies(this is not done),would like to see reduction of MAC,reduction of necrosis,but likely easier to show in animal models.It would be very difficult to enroll a biopsy study.Q:What could be the registrational endpoint for IMNM?Deba
49、ted if should get agreement on an endpoint now,but unclear would get the right one since very limited experience.Decided it is best to explore a several functional endpoints Doesnt think FDA will be dogmatic about which one specifically will be.We will look at which one has greatest benefit,smallest
50、 error bars among various ACR EULAR measures.Q:Going back,initial PNH effort didnt pan out;do you think you needed higher complement inhibition?Is it different in MG?Not fair to say PNH efforts didnt pan out A small%of pts had extravascular hemolysis,those pts stayed anemic despite hemolytic control
