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Every so often, I like to pick apart a company press release for analysis. Primarily I do this for the educational opportunity, not only for my readers but also for me. It’s a good way to catch up to what’s happening in a hot therapeutic area if nothing else. I’ve chosen Human Genome Sciences and GlaxoSmithKline’s Announcement of their initiation of a Phase 3 clinical trial of LymphoStat-B (belimumab) in Systemic Lupus Erythematosus (SLE).

Human Genome Sciences (HGSI) is a hot biotech company that was one of the pioneers [along with Incyte Corporation (INCY), Millennium et al] in decoding the human genome’s expressed sequences. They’re now trying to become a therapeutics company, and are partnered since August 2006 with GlaxoSmithKline plc (GSK) in the development and eventually the marketing of LymphoStat-B. The drug is a recombinantly expressed human monoclonal antibody, developed by HGS in collaboration with Cambridge Antibody Technologies (now part of AstraZeneca) (AZN), that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS. BLyS is a naturally occurring protein discovered by HGS that is required for the development of B-lymphocyte cells into mature plasma B cells. In autoimmune diseases, such as SLE, elevated levels of BLyS are believed to contribute to the production of autoantibodies.

SLE is a chronic, often debilitating disease, that affects primarily younger women. In the U.S., about 1.5 million people have some form of lupus; a major organ is involved in about 35% of these people. Although improved care of SLE has resulted in extensions of lifespan, current therapies are inadequate to prevent substantial morbidities, including endstage organ failure, most commonly kidney failure, from occurring in substantial numbers of patients. The subset of SLE patients with major organ involvement and active serology (i.e. autoantibodies in the blood) are the people who might eventually benefit from treatment Lymphostat-B.

The U.S. FDA has a published a draft clinical guidance for development of drugs to treat SLE, and I’ll refer to this in my comments on the announcement.

Here’s the meat of the press release, re-ordered a bit to enhance comprehension and with my commentary offset by brackets:

LymphoStat-B was generated by HGSthrough a collaboration with Cambridge Antibody Technology. It has received a Fast Track Product designation from the FDA for its potential use in treating SLE and has been selected for participation in the FDA’s Continuous Marketing Application Pilot 2 Program. The FDA has provided a Special Protocol Assessment agreeing to the LymphoStat- B Phase 3 clinical development program in patients with active SLE.

[[I’m providing links to FDA descriptions of these programs in lieu of an extensive discussion. See also my paper on the Fast Track Effect. Basically, HGStook advantage of FDA’s willingness to give feedback and prior assurances to innovators of potentially life-altering medicines. HGScan now be reasonably sure that if Lymphostat-B proves to be effective and safe in Phase 3 that they will be able to make certain pre-specified claims about the drug in their promotions.]]

Agreement has also been received from the European Agency for the Evaluation of Medicinal Products (EMEA) on the major components of the LymphoStat-B Phase 3 clinical development program, including the primary efficacy endpoint measures, target patient population, and dose selection. [[Seeing that they were falling behind the FDA in the quantity and quality of pre-submission advice being offered to applicants, EMEA improved its scientific advice program formally in April 2006. Product claims made in European countries are still subject to much more political influence than in the US, but HGS can be reasonably sure that its Phase 3 study designs will allow for EMEA approval of marketing in member states assuming the drug is safe and effective. Generally speaking, sponsors should avail themselves of both FDA’s and EMEA’s scientific advice opportunities whenever they make key product-development decisions (such as the Phase 3 decision). I’ve met more than one small-firm chief that seemed offended at the idea of taking FDA’s scientific advice. Offended or not, just get the advice and take it very seriously.]]

HGS designed the Phase 3 development program for LymphoStat-B in collaboration with GSKand leading international SLE experts. The program includes two double-blind, placebo-controlled, multi-center Phase 3 superiority trials to evaluate the efficacy and safety of LymphoStat-B plus standard of care, versus placebo plus standard of care, in the treatment of patients with active SLE.

[[HGS has wisely decided to be explicit about the use of Lymphostat-B as an add-on (i.e. adjunct) to standard-of-care (i.e. background) treatment in this release. I’ve seen in other company’s trial announcements where this isn’t as clear, and industry critics use the lack of clarity as an opportuntiy to impugn the ethics of the sponsor and study investigators, although they know full well that no IRB is going to approve a trial in active SLE without a standard-of-care offering to all participants. In this case, we’re not told whether HGS has put drug-type or dosing restrictions on the background therapy, nor is this information available in the trial registry listing. This is important to know if you are interested in comparing the treatments likely to be received by Pase 3 participants as compared with Phase 2 trial participants. Assuming that there are no restrictions on the background therapy, in order to apply the lessons of Phase 2 to Phase 3 it is necessary to understand how standards of treatment might differ at the study centers to be used for Phase 3 as compared with those used in Phase 2. It is here where you might find your luck running thin. HGS reports its investigative site locations for the Phase 3 study in the NIH clinical trial registry, but the Phase 2 study used as a basis for Phase 3 planning is not included in the registry (it should have been), nor has it been published in enough detail to know the locations of all investigative sites. You could ask HGS for this information, but they are not obliged to provide it to you. In any case, consider this issue as one of the uncertainties when transferring the Phase 2 experience to Phase 3.]]

HGS has initiated dosing in the first Phase 3 trial, BLISS-76, in which the duration of therapy will be 76 weeks. The data from BLISS-76 will be analyzed after 52 weeks in support of a potential Biologics License Application (BLA).

[[The duration of therapy of 76 weeks is presumably in response to Phase 2 data suggesting a further increase in the proportion of Lymphostat-B treated subjects achieving a global clinical response in the 24 weeks after Week 52. But keep in mind two important points. The first is that the duration of treatment used for regulatory approval will be 52 weeks, not 76 weeks. The second is that the 76-week treatment duration of the doses of Lymphostat-B being studied in Phase 3 was experienced by a relatively small number of subjects in Phase 2. This is not only because Phase 2 enrolled ~450 subjects total divided into four doses but also because switching of active-treatment doses up to the highest dose was permitted after Week 52 and switching to active drug from placebo was required. Also, the 24 weeks after Week 52 were uncontrolled, so results at Week 76 are subject to a bias not present before Week 52, a bias that would tend to favor treatment response.]]

The second Phase 3 trial, BLISS-52, is expected to begin in the first half of 2007, and will have a 52-week duration.

[[Presumably, FDA, EMEA or both asked for two adequately powered Phase 3 studies prior to approval. That’s too bad for HGS and its investors who must have hoped that a single Phase 3 study in conjunction with the results of a Phase 2 study would have sufficed for initial approval. Running two studies in parallel not only essentially doubles the cost of Phase 3 it also delays a complete regulatory filing compared with a single Phase 3 study, even if the studies finish accruing at the same time. In a perfectly efficient development organization, this shouldn’t happen; costs should increase, but overall cycle times should be the same when studies finish at the same time. But no drug development organizations are perfectly efficient.]]

The primary efficacy endpoint of both studies is the patient response rate at Week 52, as defined by: A reduction from baseline in the SELENA SLEDAI score of at least 4 points; no worsening in Physician’s Global Assessment (with worsening defined as an increase in PGA of more than 0.30 points from baseline); no new BILAG A organ domain score and no more than 1 new BILAG B organ domain score from baseline.

[[This is a complex primary endpoint that is a composite of various measures intended to gauge the activity of disease. Again, the reader takes it on faith that FDA and EMEA agreed that this primary endpoint is acceptable evidence of effcacy if demonstrated. When trying to predict efficacy in Phase 3 based on Phase 2 evidence, one should look to the effect of the drug on identical endpoints. In Phase 2, the Phase-3 dose of Lymphostat-B produced a clinically meaningful (according to experts) improvement in the proportion of responders by this composite measure.]]

Important secondary endpoints will include the patient response rate at Week 76, the SF-36 Health Survey physical component summary score, fatigue measures, and the percentage of patients with reduction from baseline in average prednisone dose at Weeks 40-52.

[[The response rate at Week 76 is not immediately relevant for approval but is likely to influence uptake. The other efficacy measures will help establish utility of the drug that can inform prescribers, patients and, importantly, third-party payers.]]

Safety and tolerability will be evaluated by an independent Data Monitoring Committee throughout both studies.

[[As is often the case with experiemental drugs, we know more about the efficacy of Lymphostat-B than we do its safety profile. HGS has said only that the drug appeared to be safe and well tolerated in Phase 2. Uncommon but serious dose-related adverse events could have been missed in Phase 2 owing to lack of power to detect them.]]

In each of the two Phase 3 trials, approximately 810 patients will be enrolled and randomized to 1 of 3 treatment groups (1 mg/kg LymphoStat-B, 10 mg/kg LymphoStat-B, or placebo). Patients will be dosed intravenously on Days 0, 14 and 28, then every 28 days for the duration of the study. To be eligible for enrollment in the Phase 3 trials, patients must be serologically active, with unequivocally positive antinuclear antibody [ANA] test results assessed at 2 independent time points (HEp-2 ANA > 1:80 and/or anti-dsDNA > 30 IU/mL). Background SLE medications must be stable for a period of at least 30 days prior to Day 0.

[[The only somewhat surprising design element here is that the companies elected to take two active doses into Phase 3. It’s obviously cheaper to study only one active dose, but perhaps regulators weren’t convinced that the lowest effective dose [LED] had been demonstrated in Phase 2. Generally speaking, clinicians like to know the LED for a drug used to treat a chronic condition; it provides them with some assurance that using a lower starting dose (e.g. for a frailer patient), or reducing the dose for a patient who experiences adverse effects at higher doses is an option supported by evidence. Drug companies often use a multiple-dose strategy for economic reasons even when studying multiple doses isn’t a regulatory requirement. It allows them pricing flexibility that doesn’t exist with only one marketed dose. For whatever reason multiple doses are being studied here, I’m a bigger fan of dose titration studies than parallel arm studies when multiple doses are taken into Phase 3. Such studies are logistically more difficult but they provide care-givers with efficacy information that is simply more relevant to practice than a parallel assignment study can offer. It looks like HGS/GSK are planning for two parallel-arm Phase 3 studies. Too bad.]]

Disclosure: Author has no position in above-mentioned companies.

Source: Glaxo and HGS's Announcement: Reading Between the Lines