Companies that emerge from academic institutions enjoy the special advantage of intimate familiarity with a new molecular entity or drug platform but also face the special challenge of contending with bigger and better financed organizations. That's true even for portfolio companies nurtured in respected biotech incubators, such as Sweden's Karolinska Development.

Aprea AB, a Karolinska company based in Stockholm, was formed more than a decade ago to advance the discovery that an initial lead compound, APR-017 (also called PRIMA-1), induced p53-mediated apoptosis by restoring p53 activity in cancer cell lines with mutated forms of the protein. The pioneering work was conducted by Klas G. Wiman, professor of molecular cell and tumor biology in the department of oncology-pathology at Karolinska Institutet, and colleagues, and published in 2002.

APR-017 belongs to a chemical class of small-molecule cancer compounds called quinuclidinones. Lead optimization with a large number of similar substances resulted in the discovery of a more potent and drug-like structural analogue of APR-017, which became the company's lead candidate, APR-246.

A two-part phase I safety study in 32 patients with refractory hematological cancer or prostate cancer met the primary endpoints of identifying dose-limiting toxicity and highest feasible dose, according to Cortellis Clinical Trials Intelligence (CTI). Part I, for which findings were published, included 22 patients. The second part included 10 patients; the main difference was a longer infusion time but the study objective was the same, according to Ulf Björklund, Aprea's chief operating officer and acting CEO.

APR-246 was reported to be safe and well tolerated, with the most commonly reported adverse events including fatigue, dizziness, headache and confusion.

The candidate showed other promising signs.

"We didn't select patients for the p53 mutation," Björklund explained. "We enrolled all kinds of refractory patients, and we could see clinical activity in these patients as well as an effect on the p53 pathway. That was very encouraging."

COMPOUND TO HELP PATIENTS 'WITH THE WORSE PROGNOSIS'

Working methodically, Aprea moved the asset through a number of preclinical studies to lay the base for further clinical development and determine the most appropriate indication. The company selected high-grade serous ovarian cancer (HGSOC) for a number of reasons, including a high incidence of the p53 mutation – more than 90 percent in those patients – as well as "a clear correlation between mutation and prognosis," Björklund told BioWorld Today.

Too, the company saw "very, very nice effects when we combined APR-246 with platinum drugs which are used in treatment of ovarian cancer," he added.

At the 2013 meeting of the American Association for Cancer Research (AACR), Aprea reported data showing APR-246 acted synergistically with platinum compounds and reversed cisplatin sensitivity to cisplatin-resistant p53 mutant ovarian cancer cells. A year later, the company presented preclinical data at AACR revealing that APR-246 was able to resensitize ovarian cancer cells to platinum compounds and doxorubicin.

That work helped to pave the way for a phase I/II study, dubbed PiSARRO (p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer), that is expected to enroll approximately 180 patients to evaluate the safety, efficacy, pharmacokinetics and pharmacodynamics of APR-246 in combination with carboplatin and pegylated doxorubicin. An open-label, multiple ascending-dose phase I study is under way to evaluate the safety and tolerability of APR-246 in combination with carboplatin and pegylated liposomal doxorubicin and confirming the dose of APR-246.

Once the top dose is reached, and pending successful completion of the initial phase, Aprea expects to initiate the randomized, controlled phase II portion of the study, which will investigate the safety and antitumor activity of APR-246 in combination with carboplatin and pegylated doxorubicin, compared with carboplatin and pegylated doxorubicin alone. The primary endpoint is progression-free survival.

To the company's knowledge, APR-246 is the only compound in the clinic that can restore normal function of mutant p53 protein and induce efficient cancer cell death, Björklund said. In January, APR-246 achieved a major milestone by receiving orphan drug designation by the EMA in ovarian cancer.

So far, studies of APR-246 have been conducted in Europe and the UK, but Aprea could seek to open an investigational new drug application in the U.S. this year.

The cancer-suppressing gene p53 is mutated in roughly half of all cancers. The resulting impairment in the suicide mechanism in the cancer cell allows tumors to grow rapidly. With the widespread occurrence of mutations in p53, the therapeutic approach of APR-246 may be applicable across a variety of cancer types, but Aprea's business model is to seek an exit – either through a license or acquisition – following conclusion of the phase II in HGSOC.

"We hope to begin development also in other indications," Björklund said. "There is a lot of interest from us and from the community to do studies in other indications, such as lung cancer, but we would need a partner for that."

Aprea's primary investor is Kdev Investments AB, a unit of Karolinska Development AB. Other investors include Swedish research funds Östersjöstiftelsen and Praktikerinvest and KCIF Co-Investment Fund KB.

The potential impact for APR-246 in ovarian cancer could be substantial, with some 600,000 women living with the disease worldwide.

Approximately 60 percent of ovarian cancer patients are diagnosed at an advanced stage, and the five-year survival rate among those patients is less than 30 percent. The company's phase Ib/II study includes ovarian cancer patients who relapsed from first-line chemotherapy – a stage where the median overall survival is 17 months.

So-called competitors in the space, including some large pharmas, are more precisely developing MDM2 inhibitors, which stabilize p53 by binding to MDM2, Björklund pointed out. That's an important differentiator for Aprea.

"We can select patients with the mutation and also with the worst prognosis," he said. "All cancer patients have a challenging prognosis, but those with the p53 mutation are among the most difficult to treat."