Novelos slides after lead drug fails Phase III lung cancer trial
This article was originally published in Scrip
Novelos Therapeutics' lead product, NOV-002, a proprietary formulation of oxidised glutathione, has failed to improve overall survival in its pivotal Phase III trial in advanced non-small cell lung cancer (NSCLC), sending the company's shares sliding by 81% to close at $0.32 on February 24th.
The randomised, controlled, open-label Phase III trial, conducted under a US FDA Special Protocol Assessment (SPA), had enrolled 903 patients with Stage IIIb/IV NSCLC. It evaluated NOV-002 in combination with first-line paclitaxel and carboplatin chemotherapy (standard doublet chemotherapy in NSCLC) versus the doublet chemotherapy alone. The primary endpoint of the trial was improvement in overall survival. The trial's statistical plan had been aiming to detect a 25% improvement in median overall survival (12.5 months versus 10 months).
Detailed trial results are expected to be presented at a scientific venue later this year.
"We are very disappointed that our pivotal Phase III lung cancer trial did not meet the primary survival endpoint," said Harry Palmin, chief executive of the Massachusetts's-based Novelos. He told Scrip that the control arm did better than expected; the trial was designed on the assumption of survival in the control arm being 10 months or less. However, he added, "There are no excuses, no dog ate my homework - the drug just didn’t show efficacy in this indication."
The company has funding into the third quarter of this year, Mr Palmin said. "It's obviously a serious setback."
NOV-002 has been approved in Russia since 2005. It is marketed there by PharmaBAM as Glutoxim. It received Russian approval on the basis of a Russian randomised Phase II trial.
NOV-002 is also in Phase II development for early-stage breast cancer and chemotherapy-resistant ovarian cancer. Novelos has a partnership with Mundipharma to develop and commercialise NOV-002 in Europe and Asia (excluding China).
Novelos' second compound, NOV-205, acts as a hepatoprotective agent with immunomodulating and anti-inflammatory properties and is in Phase Ib development for chronic hepatitis C non-responders.
mechanism
NOV-002 is a small-molecule compound based on a proprietary formulation of oxidised glutathione that acts together with chemotherapy as a chemopotentiator. Glutathione, a natural metabolite that is part of the glutathione pathway, is a determinant of intracellular redox (oxidation/reduction) potential.
Novelos' head of R&D, Dr Chris Pazoles, explained that while the reduced, tripeptide form of glutathione detoxifies cells by inactivating reactive oxygen species and may protect cancer cells from the damage induced by chemotherapy, the hexapeptide oxidised form produces a mild and transient oxidative signal which goes on to have effects on several cancer-linked cell signalling pathways through protein glutathionylation (the post-translational modification of protein cysteine residues by the addition of glutathione, which is promoted by oxidative stress). These pathways include cell proliferation and invasive pathways such as the AKT, MAP kinase, STAT and HER2 pathways. The effect on multiple cancer-associated pathways may produce a better effect than single-targeted therapies, he added.
Dr Pazoles differentiated NOV-002 from drugs that specifically raise oxidative stress levels in cancer cells to put them over the edge, such as Synta's elesclomol (STA-4783) drug, which last year failed a Phase III trial in advanced melanoma and whose development has since been suspended (scripnews.com March 3, 2009). Such drugs are like a "sledgehammer, producing more pronounced and longer lasting oxidative stress", he says, and their toxicity issues may be a result of this.
The elesclomol melanoma trial was suspended after serious safety concerns were identified, including more deaths in the experimental arm compared with the control chemotherapy arm. The effect of NOV-002 on oxidative stress is "more transient, mild and modulatory, and that distinction may be of importance for the therapeutic index of the drug", said Dr Pazoles.
However, he added that one possible reason for the failure of the trial may be that the level of desired effect was not achieved by the drug because of dosing. The other possibility is that it just didn't work in NSCLC, as the effect on redox-related endpoints is somewhat different in different tumour cell types – even though it seemed to work in earlier Phase II trials in the disease in both Russia and the US.