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C4 Therapeutics Betting on Protein Degraders to Improve Responses to Precision Oncology Drugs

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NEW YORK – C4 Therapeutics is steadily moving its BRD9- and BRAF-V600X-targeted protein degraders into the clinic hoping to demonstrate their benefits over protein inhibitors currently on the market.

C4 spun out of Dana-Farber Cancer Institute in 2015 focused on developing targeted protein degraders using technology developed by Jay Bradner, a C4 cofounder and professor at Harvard Medical School. The protein degradation technology makes use of the body's natural protein recycling system to destroy cancer driver proteins. The degrader facilitates binding of E3 ligases to the target protein, which is tagged with ubiquitin and then digested by the proteasome.

Targeted protein degraders offer several advantages over conventional small molecule inhibitors, according to C4 CEO Andrew Hirsch. One is that they completely destroy the target and repeat continuously with new targets. With a protein degrader, Hirsch said, "one can degrade thousands of target proteins," whereas an inhibitor will bind to just one protein at a time. Or, in the case of a reversible inhibitor, it may require several drug molecules to inhibit a single protein target and maintain an equilibrium that favors binding.

Another advantage of protein degraders, said Hirsch, is that they can address so-called undruggable targets. "You can get really, really unparalleled specificity around the targets, and it leads to more durable and deeper remissions, because instead of just inhibiting activity and leaving the protein there, you're destroying it," he said. "The only real escape mechanism for the protein is through protein resynthesis."

Roche, Biogen, and Calico have all recognized the value of C4's technology and have deals with the Watertown, Massachusetts-based company to develop protein degraders. The company has racked up more than $600 million since its launch eight years ago, including $73 million in Series A funding, $170 million in a Series B in 2020, $209.8 million in an initial public offering in 2020, and $180.8 million through a public offering of its common stock in 2021.

C4 uses a platform, dubbed Torpedo, to produce small molecule drugs that target proteins for degradation tailored to an E3 ligase called cereblon, which is expressed in all tissues and cellular compartments. Cereblon has been validated as a target for thalidomide and its derivative drugs including Celgene's Revlimid (lenalidomide) and Bristol Myers Squibb's Pomalyst (pomalidomide), both marketed as multiple myeloma treatments. When one of these drugs binds to cereblon, it induces degradation of key proteins leading to anti-myeloma effects of the drugs.

Knowledge of cereblon's role in the mechanisms of these drugs and its well-known reputation as a "garbage collector" without any real regulatory function gives C4 confidence about the safety profile of its drugs. "That's good because we know we're not going to mess with its natural use and have any untoward biologic implications," said Hirsch.

C4 has assembled a library of cereblon binders plus analytical tools and formulas to predict the pharmacokinetics of protein degradation using enzymology principles. The Torpedo platform can produce both monofunctional degraders, known as monodacs or molecular glues, and bifunctional degraders, or bidacs. The difference between a monodac and bidac is that the bidac has two separate binding domains for the protein target and cereblon E3 ligase, whereas the monodac has a single domain that binds both, forming a ternary complex.

With this technology, C4 is going after a wide range of targets in different cancers. One program is focused on an investigational agent, called CFT8634, which targets BRD9, a protein that plays an important role in SMARCB1-perturbed cancers, including synovial sarcoma. Inhibitors of BRD9 have been ineffective because the mechanism driving cancer involves forming a complex of more than one domain of the BRD9 molecule. "The only real way to degrade or have activity against that target is to take out the protein," said Hirsch.

C4 is studying CFT8634 in a Phase I/II trial involving patients with synovial sarcoma and other SMARCB1-null tumors who have received prior systemic therapy or who have run out of options for relapsed, refractory, or metastatic disease. Loss of SMARCB1 has been seen in synovial sarcomas, malignant rhabdoid tumors, poorly differentiated chordomas, epithelioid sarcomas, and other rare cancers, some of which are most commonly found in children and young adults. Synovial sarcomas typically affect younger adults, on average around 34 years old. Progression-free survival for patients with locally advanced or metastatic disease is about a year with traditional chemotherapy.

C4 expects to report results from this trial of its BRD9-targeting drug CFT8634 in the second half of 2023. "There has not really been advancement in the field since the '80s," said Kathleen Neville, C4's VP of clinical development. "More than half of patients with locally advanced or metastatic disease will relapse. And then, even those who survive for some time, have chemo regimen after chemo regimen."

Foghorn Therapeutics is developing a competing drug. That company began a Phase I trial of its BRD9 protein degrader FHD-609 in 2021. Neville said she believes C4 has an advantage over that product as it is administered intravenously and CFT8634 is an oral medication.

Neville said C4 is still determining what to do about companion diagnostics to identify patients eligible for its drug. Patients with SMARCB1-null tumors can be identified through fluorescence in situ hybridization or next-generation sequencing tests available through labs.

Another clinical-stage program in C4's pipeline is the BRAF V600X degrader, CFT1946. Although currently available BRAF inhibitors are effective, Hirsch noted that they only offer about 15 months of progression-free survival due to resistance mechanisms that arise during therapy. These inhibitors selectively block BRAF V600 mutant proteins, which signal as monomers. However, when these inhibitors are used to treat tumors that also contain wild-type BRAF proteins, it can drive tumor cell proliferation in what is called "paradoxical activation." Hirsch suggested that a degrader approach may overcome this and other resistance mechanisms, caused by amplifications and splice variants, for example, and "lead to deeper, more durable remissions."

C4 began a Phase I/II trial of CFT1946 in patients with BRAF V600 mutant solid tumors in January. The company will explore CFT1946 as a single agent initially in the trial and then in combination with Novartis' MEK inhibitor Mekinist (trametinib) in patients who have previously been treated with a BRAF inhibitor. 

The most common cancers presenting with BRAF V600 mutations are melanoma, and lung, rectal, and anaplastic thyroid cancers. Hirsch said the company is focused on studying CFT1946 as a second-line therapy after initial treatment with a BRAF inhibitor. Eventually, the firm hopes to add a study arm for patients who have never received a BRAF inhibitor and begin evaluating the protein degrader's potential as a first-line therapy.

"We ultimately think it will have the most utility in the front line before resistance mutations happen," said Hirsch. "But we think it can also address patients who have broken through on the first generation" BRAF-targeted therapies.

Another C4 program nearing clinical development is CFT8919, an EGFR-targeted degrader specific to the L858R mutation, the second-most common driver mutation in EGFR-driven lung cancer. Hirsch said because the molecule binds to an allosteric site created by the L858R mutation, the drug does not cause the typical side effects seen with anti-EGFR therapies. Moreover, because it doesn't bind to the same site as earlier-generation EGFR inhibitors like AstraZeneca's Tagrisso (osimertinib), it opens the door for novel combination strategies.

Hirsch said that going forward the company will lean into strategic target selection. Thus far, C4 has largely stuck with targets that are well validated with products on the market. Now that therapies produced on its platform have shown "good drug-like properties," Hirsch said the company can "start going after truly undruggable targets where no other modality can really effectively drug them and more novel targets."

Taking a precision medicine approach is integral to that vision, Hirsch added, including a patient identification strategy for each target. For C4 to back a target, Hirsch said, "it's got to be a driver of the cancer; it's got to have a clear rationale for why a degrader can do something different than an inhibitor, and can we identify patients for a precision medicine approach that we think are likely to respond?"