is an acquisition-focused biopharmaceutical company that stayed under the radar after its NASDAQ IPO in November 2011. With two notable early-stage oncology compounds in its pipeline, Clovis didn’t really attract much interest from the market until yesterday (June 3rd, 2013) – when the company reported results from ongoing Phase I/II trials for both CO-1686 and Rucaparib.
CO-1686 was originally designed by a biotech company named Avila Therapeutics, a covalent drug-focused entity that was acquired by Celgene on March 7th, 2012 in a $925 M deal. The compound was introduced to the Clovis pipeline in a $209 M partnership made in 2010 between Avila and Clovis, and the IND application was accepted not long before the company held its IPO on April 3rd, 2012.
The molecule is a covalent drug that irreversibly inhibits epidermal growth factor receptor (EGFR), which aids cancer cells in proliferation. Clovis is specifically developing it as a non-small cell lung cancer (NSCLC) treatment, since it can bypass certain obstacles in NSCLC cells that other EGFR inhibitors cannot.
Lung cancers that are caused by EGFR are initially responsive to tyrosine kinase inhibitors that can inhibit their catalytic activity, although mutations in the lung cancer cells (like the T790M resistance mutation) can ultimately shut down the viability of TKI-based mechanisms of action for drugs like gefitinib (Iressa) and erlotinib (Tarceva). Unlike other EGFR inhibitors, CO-1686 is designed to irreversibly inhibit mutated versions of EGFR, including T790M, while ignoring wild-type (normal) EGFR. This is a particularly desirable trait, since a molecule with potent and irreversible EGFR inhibition would be highly toxic to patients.
Because of this particular trait the strong safety data that Clovis reported at ASCO 2013 was particularly exciting to Wall Street. The stock moved up 104% on the Monday following the presentation, and the market capitalization of the company hovered around $2 B for the first time since Clovis’ IPO in late 2011.
Also important to the rally was the strong data that company presented for the drug Rucaparib, which is a potent PARP inhibitor – or a Poly(ADP-ribose) polymerase inhibitor being developed for breast/ovarian cancer indications. This compound was originally one of Pfizer’s oncology drugs and was named “PF-01367338” during its tenure as drug for solid tumors, although the development was handed over to Clovis in a deal announced in 2011 that gave Clovis full responsibility over the development and commercialization of the compound in exchange for an upfront payment and milestone payments of up to $255 M. This is an unusual move for an early stage pharmaceutical company, although Clovis was (and is) better-funded than most companies in the sector.
What was so exciting about the CO-1686 and Rucaparib data was that both drugs demonstrated efficacy in their respective early stage trials without reaching MTD (maximum tolerated dose). The implication is that the efficacy of these drugs may be significantly boosted in Phase II trials, which bodes well for the company’s hopes for expedited approval for its oncology pipeline.
CO-1686 was probably the more exciting of the two candidates after the results it demonstrated in non-small cell lung cancer, although optimal dosing has not been established yet. Although the drug was extremely well tolerated, the safety profile should improve as the company switches from a capsule to a tablet formulation (a move which will triple the plasma concentration of CO-1686 per dose). This may allow the company to significantly increase the already-promising efficacy. From the company’s ASCO-related press release for CO-1686:
- One patient with a del19/T790M+ tumor had progressed on erlotinib immediately before beginning CO-1686 therapy. The patient, enrolled in the 300 mg BID cohort, is currently in cycle 6 of CO-1686 therapy, with a confirmed PR
- One patient with an L858R/T790M+ tumor had received six previous lines of therapy, including two previous TKIs, dacomitinib and erlotinib, and had most recently progressed on a combination of erlotinib and gemcitibine immediately before beginning CO-1686 therapy. This patient has demonstrated tumor shrinkage in brain metastases (present at baseline), as well as lung and liver tumors. The patient, enrolled in the 900mg BID cohort, exhibited a PR in cycle 4 of CO-1686 therapy; treatment is ongoing
- One patient with a del19/T790M+ tumor had received two previous lines of therapy. This patient exhibited a PR in cycle 2 and is currently being dosed in cycle 3 at 900mg BID
- One patient with a del19/T790M+ tumor had received two lines of prior cytotoxic chemotherapy and had also progressed on erlotinib treatment. This patient exhibited a PR in cycle 2 and is currently in cycle 3, receiving 900mg BID
- Two additional T790M+ patients have achieved greater than 20 percent target lesion shrinkage with stable non-target lesions
Rucaparib, which also drew major interest, presented 89% clinical benefit rate in ovarian cancer patients across all the dosage arms, and was well tolerated with objective responses in BRCA-mutant ovarian, breast, and pancreatic cancer patients as a monotherapy. This helps to build the case that this could become a popular breast/ovarian cancer therapy that can be combined with a chemotherapeutic agent in a first-line regimen.