Bicycle Takes A Spin Into The Clinic

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Includes: AZN
by: EP Vantage

Bicycle Therapeutics' £40m ($51m) series B fundraising is impressive for a preclinical-stage UK company. But it is not a surprise to Michael Anstey of Cambridge Innovation Capital, a new investor in the company. If Bicycle's platform shows promise in humans, "I guarantee pharma partners will be interested", he tells EP Vantage.

The company's bicyclic peptides, also called bicycles, combine "the best bits of small molecules, the best bits of peptides and the best bits of antibodies", Mr. Anstey says. But with the company yet to begin human trials, it still has a long way to go. Bicycle can begin to address these bold claims once its lead asset, BT1718, enters the clinic, scheduled to happen within a year.

A bicycle is a peptide arranged around a small-molecule scaffold in two loops, explains Kevin Lee, the company's chief executive. "Because you've created loops within the linear peptide it really constrains the molecule," he says, which makes bicycles less flexible and promiscuous than regular peptides, which could in turn make them more specific.

The chief executive claims that bicycles can target "anything that a small molecule or antibody can." But the fact that bicycles are "about a hundredth of a size of an antibody" gives them advantages over antibodies including faster excretion from the body and better penetration of tissue, he adds.

Bicycles could therefore be used in areas of the body where antibody delivery is difficult. One example is the lung, and Bicycle already has a deal with Astrazeneca (NYSE:AZN) that will see the companies develop bicycles for the treatment of respiratory, cardiovascular and metabolic diseases (Snippet roundup: Deals for Boston and Astra, data for Novo and an approval for Biosurfit, December 2, 2016).

Oncology first

Although bicycles could have application in various diseases, the company has chosen to focus its resources on oncology.

The group's lead project, BT1718, is a bicycle-drug conjugate (BDC) targeting matrix metalloproteinase-14 (MMP-14), which is expressed in many solid tumors including triple-negative breast and non-small cell lung cancers. BT1718 is designed to work similarly to an antibody-drug conjugate (ADC), delivering a toxic payload to cells exhibiting this target.

BDCs could address some of the drawbacks with ADCs, Mr. Lee believes. For example, the long half-lives of antibodies can expose patients to the payload drugs for weeks or months; to avoid this problem, many existing ADCs use linkers that only release the payloads once they have been taken up by tumor cells.

There are a couple of problems with this, according to Mr. Lee. "Firstly, you can only target tumor antigens that internalise, so you're limited in the number of targets you can go after." Secondly, only tumor cells expressing that particular marker will take up the ADC, so only these will be destroyed - if the tumor also contains cells without this marker, these will survive.

Because the bicycle component of the BDC has a shorter half-life than an antibody, Bicycle does not have to use these very stable linkers, Mr. Lee says, which means the payload can be released in the broader tumor rather than within the cells.

"We're using MMP-14 as a postcode," he explains. "The BDCs rapidly penetrate the tumor, and the linkages are broken down by enzymes that are released from the tumor. The toxin is liberated inside the tumor microenvironment where it can kill all the tumor cells."

Pipeline

Bicycle also has several preclinical projects behind BT1718, and a chunk of the recent fundraising will be used to take some of these into the clinic. Mr. Lee is reluctant to give concrete details but says targets of interest include Ephrin-A2, CD137 and PD-1.

"We're exploring a PD-1 inhibitor with a very short half-life," he says. This could avoid the prolonged T-cell activation seen with existing anti-PD-1 MAbs, which can lead to autoimmune-like diseases.

How long will the £40m last? Mr. Anstey says it is less about time and more about how many projects Bicycle can progress. "The money should take the business to having two to three assets in clinic working towards approval."

In the meantime, the group could also partner with other companies outside the oncology arena. "We have to explore the full applicability of bicycles," says Mr. Lee - and collaborations could allow the company to do this without stretching itself too thinly.