Bicycle Therapeutics: Promising Early-Stage Cancer Drug Developer (NASDAQ:BCYC)

A small child fell from a bicycle onto the road, crying and screaming in pain.

JohnAlexandr/iStock via Getty Images

Bicycle Therapeutics plc (NASDAQ:BCYC) is co-founded by Nobel Prize winning molecular biologist Dr. Greg Winter, who is also its director. Dr. Winter’s involvement is majorly responsible for taking the valuation of this very early clinical stage company (with no clinical data) to a soaring $2bn last year. Undoubtedly, their science is very good – Dr. Winter is a pioneer in the therapeutics of monoclonal antibodies – however, the lack of data and a few other factors have taken the company valuation down to a relate-able $500mn now. This makes Bicycle attractive.

Bicycle is developing a new therapeutic modality called “Bicycles,” which are scaffolds of short linear peptides that stabilize their structural geometry. A biologic has broader therapeutic applicability than a small molecule. However, due to its large size, it is difficult to manufacture as well as difficult to remove from the body. Using these bicycles apparently combines the pharmacologic properties of a biologic with the pharmacodynamic and manufacturing properties of small molecules, producing the best of both worlds. These molecules have larger surface areas, which allow complex protein targets to be drugged that are not otherwise druggable with non-biological drugs. However, they are also excreted through the kidney instead of through the liver, improving their basic toxicology profiles.

Bicycle USP

Bicycle USP (COMPANY WEBSITE)

All of which is as good as the paper on which it is written until we have clinical data – and BCYC still doesn’t have any. I note three trials in the registry, all in “recruiting” stages, all phase 1 or phase 2 trials. These are:

Study BT7480-100 in Patients With Advanced Malignancies Associated With Nectin-4 Expression

Study BT8009-100 in Subjects With Nectin-4 Expressing Advanced Solid Tumors Malignancies

Study BT5528-100 in Patients With Advanced Solid Tumors Associated With EphA2 Expression

The first study will be completed in 2025, and the other two in 2023. This is the main reason the stock is trading down. A Nobel prize can only push it up so much. It can give it that initial spurt, but for long-term sustenance we need data.

There is preclinical data available which has shown that bicycle toxin conjugates or BTCs have higher potency and specificity with fewer side effects than ADCs or antibody drug conjugates. Partial data from a phase 1 study of BT8009 is available. From company material:

“BT8009 targets Nectin-4, a cell adhesion molecule from the Nectin and Nectin-like family, which has been shown to be overexpressed in tumor cells and is believed to play a role in tumor cell growth and proliferation. High in normal embryonic and fetal tissue, Nectin-4 declines in adulthood, showing a limited distribution in healthy tissues. The molecule is composed of our Nectin-4 targeting Bicycle®, a valine-citrulline, or val-cit, cleavable linker, and a cytotoxin MMAE payload.”

This partial data shows that clinical activity was seen at 5mg/m2 QW in urothelial carcinoma (UC), and the dose was well-tolerated, with signs of differentiation compared to antibodies and potential for industry-leading product profile.

• 50% ORR and 75% disease control, including 1 (13%) complete response

• Durable responses, with tumor reductions maintained over time

Toxicity profile was better in certain respects compared to Enfortumab vedotin, which is approved for advanced UC. For example, Enfortumab vedotin comes with a black box warning of severe, sometimes life-threatening skin rash; rash was present in a few cases only in BT8009, and was of low severity.

On April 11, after an initial update at AACR2, the stock went up by over 25% early in the day. But the next day, something spooked investors and the stock went down 33%. There are a number of theories about what exactly caused the fall. B. Riley analyst Kalpit Patel has one, where he spoke with a doctor who opined as follows:

The doctor was unsure of BT8009’s regulatory path and does not envision a clear route for accelerated approval, unless BT8009 demonstrates meaningful activity in other indications…

Endpoints’ John Carroll has another:

The key here is safety, where Bicycle is looking to favorably compare themselves with Padcev on Nectin-4. New questions are being asked on the safety side, though, with data on rash and neuropathy that would blur the rivalry with Seagen.

However, he seems to contradict himself in the later part of the report when he quotes Jonathan Chang from SVB Leerink, who “listened in to Bicycle’s oral presentation at AACR and noted:”

Importantly, the presentation included further granularity on the safety profile. Two adverse events in focus included rash and neuropathy, which are liabilities associated with the approved nectin-4 ADC Padcev. BT8009 demonstrated favorable rates of both of these AEs (14% BT8009-related rash, 19% BT8009-related neuropathy)… While several questions remain, particularly on the experience at the higher dose levels and additional details on safety, we believe the data overall are incrementally positive.

So what is it – is the safety data positive or is it negative?

Evaluate’s Elizabeth Cairns has another answer:

What might have startled investors was a big jump in the incidence of neuropathy, from 6% in the abstract to 24% in the AACR presentation.

However, as she rightly goes on to say:

On a call Dominic Smethurst, Bicycle’s chief medical officer, said much of the uplift was related to cases seen in non-tolerated doses that will not be pursued due to dose limiting toxicities.

The truth lies in the fact that while the company tested both the 5mg/m2 QW and the 7.5mg/m2 QW/Q2W doses, it has decided to select 5mg/m2 QW as the RP2D, the recommended phase 2 dose. You will have to look at page 19-23 here to understand the granular details, but it appears that both the QW and Q2W (once-weekly, once every two weeks) doses at 7.5 mg had safety issues, which were not acceptable given the efficacy profile at these doses.

Did this spook investors? I doubt it. There is nothing wrong with the 5mg QW dose, and its safety profile is better than Padcev’s. I am unsure if this was a retail reaction at all.

Financials

BCYC now has a market cap of $519mn and a cash reserve of $407mn. Research and development expenses were $14.3 million for the three months ended March 31, 2022, and general and administrative expenses were $17.0 million. At that rate, and given their considerable dealmaking prowess (discussed in my previous article), they have a cash runway to beyond 2024.

Bottom Line

BCYC is an interesting R&D driven company with decent cash and scientific pedigree. The current prices are low, however, this market is punishing on early-stage companies with even minor problems. I will continue to watch, but from the sidelines.

Be the first to comment

Leave a Reply

Your email address will not be published.


*