There are tough targets in drug development, and then there’s p53. It’s a holy grail, of sorts, in cancer biology—a tumor suppressor protein that gets shut down in some form in every known type of cancer. Yet every company that’s tried to protect it with a drug has failed for one reason or another.
Over the past few years, however, the tall order of shielding p53 has become the top priority of Cambridge, MA-based Aileron Therapeutics. And despite the risks, the potential reward has led to a lot of investor backing—including a fresh new round of cash today.
Aileron is announcing it’s raised another $33 million to shepherd ALRN-6924, the drug it’s developing to protect p53, into its first clinical trial. Three new backers—AJU IB Investment Co., and two undisclosed private investment groups—co-led the new funding, which Aileron is calling an “extension” to the Series E round it announced roughly a year ago. All of Aileron’s existing investors participated as well: Apple Tree Partners, Excel Venture Management, and the venture arms of GlaxoSmithKline (SR One), Roche (Roche Venture Fund), Eli Lilly (Lilly Ventures), and Novartis (Novartis Venture Funds).
The extension brings the Series E to $48 million, although CEO Joseph Yanchik says much of that has come at a valuation higher than it first expected, thanks to surprising preclinical data. When those data arrived in mid-2015, Yanchik claims Aileron tore up an earlier term sheet and built a new syndicate at better terms for the company.
“You can always extend your rounds. I think every investor syndicate approaches it the same way—it depends on who presents themselves,” Yanchik says. “In our case, the quality of the investment groups that had expressed interest and that came together as we got into the early summer was such that our investors felt that was a great opportunity to strengthen the company.”
Yanchik says Aileron has now raised “just over $100 million” since its inception in 2005. That’s a lot of cash burned, meaning it’s going to be a lot harder for Aileron’s large group of backers to generate meaningful returns.
But then again, Aileron isn’t playing safe here. It’s going for a home run, putting most of its resources behind ALRN-6924.
Though the company has a second drug candidate further along—ALRN-5281, for rare endocrine disorders—Aileron hasn’t moved it forward into a further trial since completing a Phase 1 study in mid-2013.
Instead, Aileron is assembling a team behind the p53 drug’s clinical development. Today, for instance, Aileron is naming Manuel Aivado (formerly of Taiho Oncology and GlaxoSmithKline) as its chief medical officer, and Donna Jarleneski (previously at Vertex Pharmaceuticals) as its VP of clinical operations and project management. Both have been hired to help steer ALRN-6924 forward.
“You can only take so many things into the clinic at the same time and do it well,” Yanchik says. “It is our hope to advance [ALRN-5281], and we are in a variety of discussions with interested parties that might help us do that, but right now the clinical focus is on p53.”
The big bet is that ALRN-6924 could successfully “re-activate” p53 after tumors shut it down.
The protein is bound to the DNA in the nucleus and nicknamed “Guardian of the Genome” because it’s the cell’s first line of defense. It keeps cell division in check, and when it senses something it orders the cell to commit suicide.
P53 is deactivated in every known type of cancer, either by being mutated, or repressed by another gene. Cells then start rapidly replicating, and liquid or solid tumors are formed. A drug protecting p53 could theoretically impact a broad range of cancers, which makes it tantalizing to drug makers, and clearly, to Aileron’s backers. .
Aileron believes no one else has succeeded in protecting p53 because of the limitations of antibodies and small-molecule drugs. Antibodies hit targets on the surface of cells, so they can’t make it to the proper site in the nucleus of the cell. And small molecules aren’t big enough to rip apart the protein-protein interaction that causes p53 to shut down. So the company is betting that one of its “stapled” peptides—Aileron’s core technology, through which it uses a chemical staple to keep a peptide in a specific shape—can succeed where other attempts have failed. That stapled peptide drug, ALRN-6924, is specially configured to travel to the disease site without getting chewed up by enzymes, and simultaneously hit proteins made by two genes—MDM2 and MDMX—that deactivate p53. The pharmaceutical industry, in the past, has focused on small molecules that attack only MDM2. Yanchik says, to his knowledge, no other company is using the two-pronged MDM2/MDMX approach.
There’s a long road ahead. Aileron hasn’t yet tested the drug in humans, and doesn’t have much clinical proof that its stapled peptides really work. The only human trial it has run was the Phase 1 study of ALRN-5281 in healthy volunteers.
However, Aileron is “in the final stages” of starting the first human trial of ALRN-6924. In 2013, Yanchik said he wanted to start in mid-2014 and even speculated it would recruit about 100 patients with a variety of solid and liquid tumors. That would let Aileron pick the best responders and focus on them with an additional trial arm.
When asked if there’s been a delay, Yanchik responded that the company wanted to make sure it’s going to run “as comprehensive a trial” as it could.
“Part of that involved us bringing in additional capital,” Yanchik says. “So much of the summer was spent in pulling together the financing that would allow us to do a trial that we think would really do justice to [the drug].”
Photo courtesy of May K. via Creative Commons.