The FDA advisory panel reviewing Genzyme's (GENZ) acute myeloid leukemia (AML) drug Clolar for elderly patients and Vion’s (OTC:VION) leukemia drug Onrigin did not approve either drug.
The committee recommended that a new randomized controlled trial be conducted before the drug is approved. The FDA appointed committee did not deny that Clolar might be effective in the elderly AML patients, yet its abstention from approving the drug was based on the lack of required randomized clinical trials that compare Clolar to other drugs, which is considered a necessity for cancer drug approval. It is a matter of principle that guidelines must be followed, but Genzyme has not.
Maybe Genzyme tried his luck in obtaining an early approval for the elderly. Or maybe it felt it does need approval because Clolar is already marketed for pediatric AML patients and that oncologists can use it off-label to treat the elderly AML patients too, if they wish. All do not matter now. What matters is that, sooner or later, Clolar will be approved for the elderly. The truth is that Genzyme is, indeed, conducting randomized, controlled studies on Clolar on this group of elderly AML patients, but did not wait for the results to come out before it submitted its application for approval. This is Genzyme.
Clolar is a hybrid of fludarabine and cladribine -- synthesized as a rational extension of these analog experiences. Purine nucleoside analogs such as cladribine and fludarabine are among the most widely used agents in leukemias. However, they are not generally used as single agents, and are used at dose levels associated with neurotoxicities. An addition to the purine nucleoside analog family, Clolar has shown favorable activity as a single agent in pediatric relapsed and refractory ALL. In vitro studies suggest Clolar retains the 2-halogenated adenine of both fludarabine and cladribine, which makes it resistant to deamination, and also incorporates fluorine to make the glycosidic bond resistant to phosphorolysis, which limits the release of halogenated adenine4,5.
Onrigin, developed by Vion also for elderly high-risk patients with acute myeloid leukemia (AML) has faced the same FDA committee and received the same answer as Genzyme - NO. The reason for the denial of approval is the same as the one given to Genzyme - lack of randomized trials.
Onrigin targets very sick patients with many vulnerabilities, which make their disease untreatable by conventional chemotherapy drugs. As a matter of fact, Onrigin had good results, a 32% remission rate with median overall survival greater than one year.
The fourteen percent of patients who died within a month of treatment with Onrigin are not different from the percentage of death experienced with other drugs used to treat these patients. Lung toxicity and higher infection rates were no news, as the recruited patients were in bad shapes when entered the trials. The bad news for Vion is that the panel believed that the patients who did well on Onrigin were likely healthy enough to be treated with standard chemotherapy and get the same results. As fifty percent of the responding patients have also been treated with another chemotherapy drug in addition to Onrigin, which makes it difficult to separate out the contribution of Onrigin.
Moreover, the responses in Onrigin-treated patients were brief, with 38% lasting less than 90 days.
Toxicity associated with Onrigin was discussed at length, especially the side effects that caused death. Without a randomized controlled trial, the FDA group believes it is difficult to pinpoint the origin of the lung toxicity.
The verdict? The same as that given to Genzyme, i.e., recommending that Vion conducts a randomized controlled study in elderly, high-risk AML patients.
Allos (NASDAQ:ALTH) and the Tough Committee
Today, it is Allos Therapeutics’ turn to face the same committee. Many analysts and investors believe, though, that this time, Allos’ peripheral T-cell lymphoma (PTCL) drug pralatrexate will be approved. Other less optimistic analysts wonder whether the drug can make it to the market with only a single-arm pivotal trial that was cause for rejection of the two leukemia drugs by the same committee.
The optimistic analysts rely on the fact that Allos had reached an agreement with the FDA on the design of the non-controlled pivotal trial for pralatrexate in patients with peripheral T-cell lymphoma (PTCL). Genzyme and Vion did not have the same advantage with regard to their leukemia drugs. The less optimistic and the pessimist come from the fact that they learned not to trust the FDA on any promise that relates to drug approvals.
Putting aside the story of the special protocol, which the optimist expects to save Allos’ today and base our speculation on the trial data, we can say with fairness that pralatrexate has demonstrated efficacy. Yet, we can also observe that the results have holes. These holes would probably raise many questions in the committee’s mind that will be expressed with their tongues, which might lead to arguments that could infuriate the committee’s extreme conservative members. These members still have the right to recommend another trial like they did to Genzyme and Vion. Another more optimistic scenario is that the committee would stop short of asking for new trials based on the FDA granted special protocol assessment. Or better even, if the members take in consideration the fact that the disease targeted by pralatrexate, i.e., peripheral T-cell lymphoma (PTCL) is deadly and has no specific treatment. In such a scenario the outcome of the meeting could be nicer than the outcomes of the review for Genzyme’s and Vion’s leukemia drugs.
This would be very good news for Allos.
Disclosure: No Positions