Specialist
Adjunct Professor at Johns Hopkins University
Agenda
- Overview of the bispecific antibodies industry and mechanisms of action, including evaluating BiTEs (bispecific T-cell engager) and DARTs (dual-affinity retargeting antibodies)
- Deep dive into Johnson & Johnson’s (NYSE: J&J) Rybrevant (amivantamab-vmjw), Amgen’s (NASDAQ: AMGN) Blincyto (blinatumomab) and Roche’s (VTX: ROG) Hemlibra (emicizumab)
- Evaluation of existing drugs’ trial data and market viability
- Bispecific antibodies market outlook
Questions
1.
J&J’s [Johnson & Johnson’s] Rybrevant [amivantamab-vmjw] is the most recent of the three bispecific
antibodies approved by the FDA. Rybrevant is the first and only antibody treatment designed to target
mNSCLC [metastatic non-small-cell lung cancer], with the EGFR [epidermal growth factor receptor] exon 20
insertion mutation. What are your thoughts on Rybrevant’s structure and its mechanism of action? What is
the significance of the EGFR exon 20 insertion mutation, as well as the MET domain? Clients, I would
recommend the previous Interview [see Bispecific Antibodies – Market Opportunity & Competitive
Landscape – Part 1 – 21 December 2021] to read what we’ve already covered.
2.
Asymmetrics such as Rybrevant have potential to overcome some of the challenges with symmetric
antibodies, but I understand they’re very difficult to develop and manufacture. How might J&J have dealt with
challenges with asymmetric vs symmetric, or is my understanding of that process dated?
3.
The FDA granted an accelerated approval of Rybrevant on 21 May 2021, following the CHRYSALIS trial, a
study of 81 patients with NSCLC with the EGFR exon 20 insertion mutation, with the primary endpoint being
ORR [objective response rate]. Could you discuss the CHRYSALIS trial and share your thoughts on
Rybrevant’s efficacy and its safety and tolerability profile, as well as the CR [complete response] vs PR [partial
response]? I was surprised at how weak the CR was. What are the most common adverse effects?
4.
What are your thoughts on Rybrevant’s market potential? This would have to be a monstrous launch to get
mentioned by J&J and unsurprisingly it wasn’t. Could it take off or might its success be short-lived, given
competitive TKIs [tyrosine kinase inhibitors] down the road that are trying to overcome some of their
shortcomings, in terms of the refractory issues?
5.
Do you think Rybrevant will take significant market share from the approved TKIs, even though it’s a small market?
6.
Amgen’s Blincyto [blinatumomab] was approved by the FDA for B-cell precursor ALL [acute lymphoblastic
leukaemia] in first or second complete remission, as well as relapsed or refractory precursor ALL. Blincyto is a
BiTE [bispecific T-cell engager]. Could you describe what BiTEs are and comment on what I consider an
enormous potential in oncology, given the broad set of cancer types as well as the robust range of targeted
antigens?
7.
Could you elaborate on activating T cells, released cytokines and the production of additional perforin and
granzymes? I personally feel BiTEs are fascinating and the versatility is phenomenal, and I’d like to get to
some more of the different cancers such as multiple myeloma, ALL and AML [acute myeloid leukaemia], and
why we can attack all those, whether we’re using BCMA [B-cell maturation antigen], CD19 or CD33, as well as
FLT3 and DLL3. Could you discuss some of those nuances and what you’re most excited about across all those
targets?
8.
Let’s discuss the issue of clearance, because some of these BiTEs are being engineered to be cleared quickly through the body with a typical half-life of just a few hours. There are real benefits to that clearance, but there is also real detriment if patients have to be constantly infused. That’s why BiTEs are also being designed with these Fc [fragment crystallised] domains, to extend the time before they’re eliminated. I had read that mutating the Fc, which is the bottom portion of the Y vs the prong portion, can reduce half-life. What are the pros and cons of fast clearance vs extending half-life and how is that being tackled?
9.
Based on Amgen Q3 2021 report, Blincyto had just USD 125m sales. This seems disappointing to me as this
drug was approved in 2014. Is that a disappointment? What’s happening? I appreciate this isn’t marketmoving given Amgen’s Q3 quarterly revenue was just over USD 6.7bn. However, Blincyto’s revenue did
increase 40% YoY and so while that growth rate is impressive, it is such a small amount of Amgen’s revenue.
How should we think about this drug? Has it been successful or a failure?
10.
Roche’s Hemlibra [emicizumab] was approved by the FDA in October 2018 for haemophilia A without
factor VIII inhibitors. This approval was based on positive results from the phase 3 HAVEN 3 and HAVEN 4
studies. The drug generated CHF 2.2bn in the first nine months of 2021, up 42% YoY from the nine-month
period in 2020. Could you explain the drug’s design, its mechanism of action and your thoughts on the efficacy
and safety?
11.
Could you walk us through DARTs [dual-affinity retargeting antibodies]?
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