New Drug Approvals In 2003 Could Include Four HIV Agents

FDA's new molecular entity approval totals for 2003 could feature as many as four novel HIV agents.

The four new HIV drug candidates include two protease inhibitors (Bristol-Myers Squibb's atazanavir and GlaxoSmithKline's Agenerase prodrug fosamprenavir), one nucleoside reverse transcriptase inhibitor (Triangle's Coviracil ), and one fusion inhibitor (Roche/Trimeris' Fuzeon ).

The next HIV drug approval will end one of the category's longer dry spells in the last decade. The last antiviral to treat HIV approved by FDA was Gilead's Viread (tenofovir) on Oct. 26, 2001.

In addition, the approval of Fuzeon (T-20, enfuvirtide) would mark the first new class of anti-HIV agent since the approval of the first protease inhibitor, Roche's Invirase (saquinavir), in December 1995.

Before 2002, the last year in which FDA did not clear an antiviral for AIDS was 1993.

One of the NMEs cleared in 2002 - Gilead's Hepsera (adefovir dipivoxil) - was originally developed as an HIV agent, but was rejected due to toxicity concerns. The product cleared FDA Sept. 20 at a lower dose for treatment of hepatitis B.

Another NME approved in 2002, Pfizer's antifungal Vfend (voriconazole), is indicated for use in treating infections often associated with AIDS. Romark's Alinia (nitazoxanide), which was approved Nov. 22 for the treatment of pediatric diarrhea associated with Cryptosporidium and Giardia, was first submitted in 1997 for treatment of cryptosporidiosis in HIV patients.

The prospects for multiple HIV drug approvals in 2003 after an unusual paucity in 2002 may set the tone for the overall climate for NMEs. In terms of numbers of approvals, 2002 was a dismal year for the pharmaceutical industry - but the outlook appears brighter for 2003.

Only 17 NMEs were approved in 2002, down from 24 in 2001 and 27 in 2000. The 2002 total marks the lowest number of approvals since 1983, when 14 NMEs were approved.

The total is less than one-third of FDA's all time high of 53 NME approvals in 1996.

However, the stage appears to be set for 2003 to be a rebound year. The agency is entering the year with at least 21 pending NME applications that appear to have a chance at approval (¹ see chart).

An upturn in NME approval totals would be in keeping with historical precedent, since 2003 will be FDA's first full year under Commissioner McClellan.

During Commissioner Young's first full year in 1985, FDA's NME count jumped from 22 to 30. The same pattern held in 1991, Commissioner Kessler's first full year, when NMEs jumped from 23 to 30. Even in the user fee era, there was an uptick during Commissioner Henney's first year (1999) from 30 to 35.

While FDA is likely to exceed the 17 NME approvals in 2002, it appears unlikely to approve anywhere close to 30, barring a sudden and unexpected rush of new filings early in the year.

The low number of NME approvals in 2002 appears directly linked to a low number of submissions, and not to any increase in rejections or deferrals on the agency's part.

By Sept. 16, FDA had received only 16 NME submissions in fiscal 2002, half the level of the previous two fiscal years.

As of Dec. 15, only 14 NMEs had been filed in calendar 2002.

However, a rush of end-of-the year filings will boost the final calendar 2002 submission total significantly. At least one-quarter of 2002 submissions were filed in the last two weeks of the year (see related story on ² (Also see "December's 5 NMEs Filings: Ranexa, Certican, Memantine, 2 HIV Drugs" - Pink Sheet, 1 Jan, 2003.), p. 7).

Late-2002 filings included atazanavir, fosamprenavir, Novartis' cancer agent Certican (everolimus), Forest's Alzheimer's agent memantine, and CV Therapeutics' chronic angina agent Ranexa (ranolazine).

The end-of-the-year filing rush parallels the pre-user fee phenomenon of a December drug approval rush, when it was not uncommon for as many as one-half of the total number of NMEs to clear FDA in the last weeks of the year.

Given the 10-month standard review deadline, October may soon emerge as FDA's busiest month.

The NME approvals continue to be backloaded in the year. FDA cleared 11 of the 17 approved NMEs during the third and fourth quarters. The largest number of approvals was granted during the fourth quarter, with six NME clearances.

December was a relatively quiet month, with only two NME approvals (Pfizer's Relpax and Baxter's Extraneal ).

Another therapeutic category that could see a lot of approval activity in 2003 is erectile dysfunction. Pfizer's Viagra (sildenafil) could face competition from up to three new oral agents, including two in the PDE-5 inhibitor class.

TAP resubmitted the dopamine agonist ED agent Uprima (apomorphine) Oct. 25, setting a user fee goal date in August.

Lilly ICOS' Cialis (tadalafil) has been "approvable" since April 29. The agency requested further pharmacology studies; Lilly expects the drug to be approved during the second half of 2003. Cialis is racing against Bayer/GlaxoSmithKline's Levitra (vardenafil), which was made "approvable" July 23.

Other commercially significant "approvable" drugs at FDA that could join the approval class of 2003 include AstraZeneca's cholesterol agent Crestor (rosuvastatin), Lilly's antidepressant Cymbalta (duloxetine), and Aventis' antibiotic Ketek (telithromycin).

The COX-2 inhibitor class could receive another member with the approval of Novartis' Prexige (lumiracoxib). The arthritis agent was submitted in November.

Boehringer-Ingelheim's chronic obstructive pulmonary disease therapy Spiriva (tiotropium) could also clear the agency in 2003. The NDA was submitted Dec. 13, 2001; FDA's Pulmonary-Allergy Drugs advisory committee agreed that Spiriva was efficacious for bronchodilation but not dyspnea.

Finally, two chemotherapy-induced vomiting and nausea treatments could receive approval in 2003. Merck's Emend (aprepitant) was submitted during the second half of 2002 and MGI Pharma's palonosetron was submitted Sept. 27.

The average total approval time for the 17 NMEs cleared by FDA in 2002 was 17.0 months.

The 2002 NME average approval time is lower than the 18.5-month average for NMEs in 2001, and the 17.2-month average for 2000. However, the 2002 average is not as low as the 1998 and 1999 NME times of 12.9 and 12.5 months.

The apparent decrease in total approval time may help FDA refute industry assertions that the recent "slowdown" in R&D productivity is due to FDA's extended review periods.

However, of the 17 new molecular entities approved during 2002, only two applications (Pharmacia's antihypertensive Inspra and Schering-Plough/Merck's cholesterol agent Zetia ) were approved on the first cycle, without receiving an extension, an "approvable/
not approvable" action letter, or being resubmitted (see related story on ³ (Also see "FDA Approval Is "First Action" For 32% Of NMEs; Rate Less Than Other NDAs" - Pink Sheet, 1 Jan, 2003.), p. 19).

Zetia technically had the shorter review: it was approved two days before the 10-month user fee deadline. Inspra was approved one day before the deadline.

Thirty percent of the NMEs approved in 2002 required resubmissions to the agency for approval. The resubmissions had the effect of reducing the average approval time for NMEs significantly because of short reviews following refiling with the agency.

For example, Sanofi-Synthelabo's cancer agent Eloxatin (oxaliplatin) had the unusually short review time of 1.5 months.

The Eloxatin NDA was originally submitted in July 1999 for a first-line colon cancer indication, but the drug received a second-line indication after resubmission in June 2002.

The drug's time to approval would have been 36.6 months if calculated from original submission until final approval. That calculation makes Eloxatin the second longest approval time for the year rather than the shortest.

If approval time was calculated for all 17 NMEs from the date of first filing, the average time would have been 25.2 months.

Without the five resubmitted NMEs, the remaining 12 NMEs approved in 2002 would have had an average approval time of 20.8 months.

The average time for approval from NDA resubmission for the five remaining NMEs was 7.8 months. However, the total approval time from an original submission for the five drugs averaged 35.7 months.

Four of the drugs were resubmitted for substantially similar indications as the original applications. Only Hepsera was resubmitted for an entirely different indication.

Excluding the resubmitted applications, Zetia (ezetimibe) received the shortest review, with an approval in 9.9 months, just under the 10-month user fee goal date.

The longest approval time was 50 months for Pfizer's migraine agent Relpax (eletriptan). The NME was submitted Oct. 27, 1998, and was "approvable" in October 1999 and December 2000.

FDA took a first action - issuance of a "complete review" or approval - on all NMEs in an average of 9.1 months, a decrease from the 10-month average first action time of 2001, as calculated by Pharmaceutical Approvals Monthly.

For standard NME reviews, the average first action time was 11.3 months, a decrease from the 11.8 months seen in 2001. For priority reviews, the average first action time was six months, down from 8.3 months in 2001.

FDA took action on 50% (5/10) of the standard NMEs within 10 months, compared to 29% in 2001. Thirty percent of the standard applications received approval as FDA's first action, as compared with 29% in 2001.

For priority NMEs, the agency took action on 71% (5/7) of the applications within six months, compared with 86% (6/7) in 2001. Only 43% (3/7) of the priority reviews received approval as FDA's first action, as compared with 57% (4/7) in 2001.

FDA has previously acknowledged that its efforts to meet PDUFA goals may have had the "unintended consequence" of increasing drug approval times as more applications are receiving multiple review cycles.

The average approval time for the 10 standard review NME applications in 2002 was 20.3 months, an improvement over the 22.8 months required for approval of the 17 standard NME applications in 2001.

Average approval time for priority review NMEs, however, increased. The seven priority review applications of 2002 were approved in an average 12.3 months, compared to 8.3 months for the 10 priority NMEs approved in 2001.

Pfizer was the only company in 2002 to see more than one NME clear FDA: the antifungal Vfend and the migraine drug Relpax.