Editor

BioCryst Pharmaceuticals Inc.'s stoppage of the Phase IIb program with intravenous Fodosine gave investors the shivers regarding plans for an oral version in a separate indication, but they probably need not worry too much - at least, not for the same reasons.

The company backed off developing IV Fodosine (forodesine) in T-cell acute lymphoblastic leukemia/lymphoma (T-cell ALL) because of lower-than-hoped-for efficacy and because of unstable drug batches, possibly due to something in vial lids interacting with a substance in the solution.

A finished Phase IIa trial in T-cell ALL likely will show a lower final response rate than the 18 percent reported from interim data at the American Society of Hematology, BioCryst said, since none of the newer trial entrants turned out to be responders - possibly because they got Arranon (nelarabine, from GlaxoSmithKline plc) as background therapy.

With oncology partner Mundipharma International Holdings Ltd. (which pays for Fodosine's overseas development and reimburses an undisclosed portion of domestic costs), BioCryst is figuring out the next steps with the oral form of the compound for cutaneous T-cell lymphoma (CTCL), possibly taking a quicker route to market.

It's a route marked by footprints of Merck & Co. Inc., which in October won approval of the first histone deacetylase inhibitor to be cleared in the U.S.: Zolinza (suberoylanilide hydroxamic acid, once known as SAHA) for cutaneous T-cell lymphoma. Merck acquired Zolinza in its 2004 buyout of Aton Pharma Inc.

Analyst Vinny Jindal with ThinkEquity Partners found the similarities worth noting.

Fodosine first was tried in a dose escalating Phase I CTCL trial in which 13 patients got 40 to 135 mg/m 2 of drug via IV every 12 hours for 9 treatments. Positive data caused BioCryst to do a dose-ranging Phase I/II trial with the oral form. In the Phase I dose-escalation part, the maximum tolerated dose was not reached, with no toxicities. In the Phase II part, 34 patients with refractory CTCL got the drug once daily (80mg/m2 or 160mg/m2) for at least 28 days, with a median treatment time of 18.6 weeks. The overall response rate in this study was 50 percent, including three patients with complete response and 14 patients with partial response. The objective overall response rate among late-stage patients was 52 percent, and the median time to response was 47 days (14 days to 112 days), with a median duration of response reaching 85 days.

Zolinza, before it was given the FDA's blessing, was tested in 107 CTCL patients in two single-arm, open label, non-randomized studies. In the pivotal trial, 74 patients with relapsed/refractory advanced CTCL who had previously failed at least one therapy were treated with 400mg of oral Zolinza daily. The objective response rate was 30 percent, with one complete responder, and the median time to response of 56 days. In the dose-escalation trial, 33 patients with refractory CTCL were assigned to one of three dose cohorts. The objective response was 24 percent, 25 percent in patients with advanced disease, and 36 percent in patients with Sezary syndrome (a variant of CTCL in which cancerous T-lymphocytes affect the skin). Median time to response was 83.5 days and response duration 106 days.

Given Zolinza's success, some are more optimistic about Fodosine's chances. BioCryst entered the potential $190 million Mundipharma deal at the start of the year, granting exclusive development and commercialization rights to Mundipharma for Europe, as well as markets in Asia and Australia, including Japan, New Zealand, China and India. In exchange, BioCryst got a $10 million up-front fee, plus up to $155 million in milestone payments. Mundipharma also is funding up to $10 million to assist with BioCryst's ongoing development work on Fodosine, and another $15 million for near-term development efforts in Europe.

A potential problem cited by analysts for BioCryst (and others) involves changes at the FDA - changes that recently caused some of Hana Biosciences Inc.'s troubles. Late last year, Hana sought a special protocol assessment from the agency regarding the first of two Phase II, open-label, potentially pivotal trials of Marqibo (vincristine) in acute ALL. Weeks ago, Hana got a letter from the FDA noting that the Office of Oncology Drug Products has implemented a policy restricting SPAs to randomized trials.

Jim Alexander, chief medical officer at BioCryst, told BioWorld Financial Watch that the CTCL trial protocol submitted to the FDA for SPA consideration (before Hana's problem surfaced) is non-randomized, and BioCryst is "actively" working to determine whether the agency's apparent new rule will apply.

"We're not going to wait 45 days," he said, citing the period the FDA has to review the request. "I don't think [the agency has] decided to limit [the rule] to one company," Alexander said, although "certainly we have a different drug [from Hana's], and I'm sure our protocol is different."

Andrew Fein, analyst with C.E. Unterberg, Towbin wrote in a research note last week that he was unsure whether the protocol in the SPA for BioCryst's CTCL trial called for a randomized trial but, "should the protocol be for a non-randomized trial, we view it likely that the SPA will not be granted."

The good news for Fodosine, a transition-state analog inhibitor of purine nucleoside phosphorylase, is that the oral form will not plagued by the instability of the IV batches. Not only this, but the CTCL indication (though characterized by abnormal T-cell lymphocytes) seems well distinguished from T-cell ALL. CTCL occurs mainly in people age 50 to 60, whereas T-cell ALL tends to strike younger ones.

The CTCL market is much bigger, too, with about 16,000 cases per year in the U.S., compared to 1,000 cases of T-Cell ALL, and oral administration means a perfect therapy for outpatients.

BioCryst has more in its hopper, including peramivir, a Phase II neuraminidase inhibitor with fast-track designation from the FDA for flu. In February, the firm was awarded a piece of the venture capital firm Kleiner Perkins Caufield & Byers' $200 million Pandemic and Bio Defense Fund for work with peramivir.

KPCB has provided money for entrepreneurs behind the likes of Genentech Inc. and Idec Pharmaceuticals Inc. (now Biogen Idec Inc.), as well as AOL, Amazon.com and Google. The avian-flu threat likely will keep eyes on peramivir. Preliminary data are expected by the middle of this year, and final data by the end of the year.

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