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1、9 March 2020Global ResearchGlobal HealthcareFuture of Gene Therapy I: Scoping therapeutic challenges and demystifying manufacturingEquitiesGlobalHealthcareDevelopment of in vivo gene therapies is intensifyingParadigm-shifting in vivo gene replacement products like Novartis, Zolgensma are coming to m
2、arket. Here we attempt to highlight some of the challenges and key questions in this area both near term and on a longer term view. In particular, we have taken a deep dive with industry and academic experts to demystify manufacturing considerations for AAV viral vectors (delivery systems), screened
3、 100+ monogenetic diseases for R&D activity, examined the ways large biopharma companies are building platforms including speaking with management and looked for evidence of future directions in pricing, technological development and therapeutic potential.The supply and demand imbalance for viral ve
4、ctor manufacturing is worsening Manufacturing is tightly integrated with R&D for gene replacement products because their end capabilities are in part dictated by how they are made. cGMP capability is required and there are severe bottlenecks in supplying companies that cannot produce in house. Capac
5、ity is growing far more slowly than INDs for new therapies and our rough calculations suggest demand can increase more than 20x when production is stepped up to commercial levels. Paragon (CTLT) and Brammer (TMO) are two leading US-based CDMOs and diligence suggests solid competitive positioning. Lo
6、nza also plays here. Feedback reflects DHR and GE being well positioned on the tools side, along with TMO and SRT, with CRL a leading testing player. AVTR has exposure for excipients.In the short term we expect pricing in hemophilia A to be controversialBioMarins valrox is in regulatory review with
7、a decision due in August. High prices have been mentioned, possibly higher than the $2.1m for Zolgensma but with uncertainty over duration and others following into the space we think payer impetus to implement long-discussed outcomes based payment models is probably increasing.In the longer term qu
8、estions around broadening applicability are relevantGene editing is now in the clinic but we think it still has a long way to go and do not see gene replacement therapy becoming obsolete in the near future. Mass application in diseases where genes are factor but not a clear root cause is also hard t
9、o envision at this stage but experts we have spoken with agree that building on todays technology, e.g. by removing a gene then replacing it, looks plausible.Laura Sutcliffe, PhD Analyst +44-207 568 6240Dan Brennan, CFAAnalyst +1-212-713 2317Michael Leuchten Analyst +44-20-7568 8843Navin Jacob Analy
10、st +1-212-713 6185Kevin Caliendo Analyst +1-212-713 3630Andrew Frost Analyst +44-20-7568 2587Nathan Trey beck Associate Analyst +1-212-713 2392Petrina-Oana Carcota Analyst +44-20-7567 7335John Sourbeer Analyst + 1-212-713-7983Jonathan Lim Associate Analyst + 1-212-713 4321This report has been prepar
11、ed by UBS AG London Branch. ANALYST CERTIFICATION AND REQUIRED DISCLOSURES BEGIN ON PAGE 42. UBS 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 thi
12、s report. Investors should consider this report as only a single factor in making their investment decision.trial and another developed leukemia after chromosomal integration of a retrovirally delivered gene occurred into an oncogene), halted the fields progress. The number of clinical trials initia
13、ted remained relatively flat from 1997 through to c.2012 as a result.Recent improvements in both the safety and efficacy of vectors have driven a dramatic upward inflection with trial initiations more than doubling over the past six years.No. of gene therapy trials per year: flat 1997-2012 (safety),
14、 rapid growth sinceSource: Gene Medicine; Updated Dec 2018; arrow added by UBSWhat makes an ideal vector?Several considerations go into choosing the best vector for gene transfer: Is the target condition associated with rapidly dividing cells (needs a vector that integrates the new material into the
15、 host genome to ensure persistence) or relatively static cells (which allow for a non-integrating vector)? How big is the gene that needs to be transported? Which vectors can best target the desired cell types? Which vectors can deliver genes (transduce target cells) most efficiently? How safe and /
16、 or immunogenic is the vector? How convenient and reliable/reproducible is the method of production?Vectors can be broadly classified into three categories:(1) Non-viral - e.g. plasmid (and also liposome + plasmid)(2) Viral (DNA) - Adenovirus and adeno-associated virus(3) Viral (RNA) - Retroviruses, including lentiviruses which are
