July 2012

26 July 2012

Vivus’ Qsymia (formerly Qnexa) approved by the FDA–the most efficacious weight-loss drug ever approved in the U.S.

By Allan Haberman, Ph.D|2018-11-14T00:20:06+00:00July 26, 2012|Drug Development, Metabolic diseases|

Qsymia (phentermine/topiramate CR)

On July 17th, 2012, Vivus, Inc. (Mountain View, CA) announced that the FDA has approved its antiobesity drug, Qsymia (phentermine and topiramate extended-release). This is the second antiobesity drug–after lorcaserin (Arena/Eisai’s Belviq)–to be approved in 13 years. Belviq was approved just last month; this was the focus of our June 30, 2012 Biopharmconsortium Blog article.

As discussed in that article, both Belviq (formerly Lorqess) and Qsymia (formerly Qnexa) were two of the three members of what we called the “Class of 2010” of CNS-targeting antiobesity drugs. All three of these drugs (which also included Orexigen’s Contrave) had come up for review in 2010, and were rejected by the FDA, mainly due to concern about the drugs’ long-term safety. After the companies conducted the further studies prescribed by the FDA in 2010, two of these drugs, lorcaserin and Qsymia–had received positive votes by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, as of May 2012. Then lorcaserin was approved in June 2012, and Qsymia in July 2012.

The FDA approved Qsymia as an adjunct to diet and exercise for chronic weight management in adult patients who are obese [initial body mass index (BMI) of 30 kg/m2 or greater], as well as for overweight patients with a BMI of 27 kg/m2 or greater who also have at least one weight-related comorbidity, such as hypertension, dyslipidemia, or type 2 diabetes. This is the same population for which the FDA approved Belviq last month.

According to Vivus’ President, Peter Tam, Qsymia is the “first FDA-approved once daily combination treatment” for obesity. In contrast, Belviq must be taken twice a day, and is a single-agent drug.

As we discussed in our August 4, 2010 article on this blog, Qsymia (then called Qnexa) is a low-dose, controlled release (CR) formulation of two previously FDA-approved drugs: phentermine (PHEN) and topiramate (TPM). Qsymia was designed to both suppress appetite (phentermine) and promote satiety (topiramate).

Phentermine, an amphetamine, has been prescribed as a weight-loss aid that is used short-term. It was the “phen” half of the notorious “Fen-Phen” combination. The “fen” part, fenfluramine (Pondimin) or dexfenfluramine (Redux), were serotonin modulators that caused cardiovascular side-effects. Topiramate is an anticonvulsant. As separate agents, phentermine and topiramate have minimal effects on weight loss. However, according to Vivus’ studies, the two drugs appear to have a synergistic effect, even at low doses, that results in significant weight loss. Vivus’ studies also indicate that the two drugs mitigate each other’s side effects; the low does and controlled release is also designed to reduce side effects.

Adverse effects of phentermine may include increase in blood pressure and heart palpitations, as well as gastrointestinal side effects. Side effects of topirmate may include cognitive issues, lack of coordination, aggressiveness, changes in ability to taste food and loss of appetite, cardiovascular side effects, and others. As of the August 4, 2010 publication date of our initial blog article on Qnexa/Qsymia, the risk of birth defects with ether of these drugs was unknown. However, there was preliminary evidence that topiramate might cause birth defects. More recently, on March 4, 2011, the FDA warned of an increased risk of development of cleft lip and/or cleft palate (oral clefts) in infants born to women treated with topiramate during pregnancy.

Results of Phase 3 clinical trials with Qsymia

According to the July 17th, 2012, Vivus announcement, the safety and efficacy of Qsymia were evaluated in two multicenter randomized controlled phase 3 trials. These included the EQUIP study with severely obese patients, and the CONQUER study with overweight or obese patients with at least two weight-related comorbidities (e.g., hypertension, hypertriglyceridemia, type 2 diabetes, or central adiposity) that are related to the metabolic syndrome.

In the 56-week EQUIP study, adult male and female patients with a BMI ≥ 35 kg/m2 were randomized to placebo, PHEN/TPM CR 3.75/23 mg, or PHEN/TPM CR 15/92 mg; all patients were also on a reduced-calorie diet. The average weight loss was 10.9% of body weight for the high-dose Qsymia (PHEN/TPM CR 15/92) group and 1.2% for placebo. 66.7% of patients on high-dose Qsymia lost at least 5% of body weight, as compared to 17.3% for placebo. The difference between the Qsymia and the placebo groups were statistically significant. The high-dose Qsymia group also has significantly greater changes relative to placebo for waist circumference, blood pressure, and fasting blood glucose, triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL).

In the 56-week CONQUER study, adult male and female patients with a BMI of 27-45 kg/m2 and two or more obesity-related comorbidities were randomized to receive either placebo, PHEN/TPM CR (7.5/46 mg), or PHEN/TPM CR (15/92 mg). The average weight loss was 9.8% on PHEN/TPM CR (15/92 mg) {“high-dose Qsymia”), and 1.2% for placebo. The differences in weight loss between the treatment arms and the placebo arms of these studies were statistically significant.

21% of patients lost at least 5% of body weight with placebo, and 70% of patients patients lost at least 5% of body weight with high-dose Qsymia. For percentages of patients who lost over 10% of body weight, the corresponding numbers were 7% and 48%. These differences were also statistically significant.

The most common adverse reactions for patients treated with Qsymia included tingling sensation of hands and feet, dizziness, altered taste, insomnia, constipation and dry mouth.

Risk Evaluation and Mitigation Strategy for Qsymia

The FDA approved Qsymia with a Risk Evaluation and Mitigation Strategy (REMS). The goal of the strategy is to inform prescribers and women patients of reproductive potential about an increased risk of orofacial clefts in infants exposed to Qsymia during the first trimester of pregnancy, the importance of pregnancy prevention for females of reproductive potential receiving Qsymia and the need to discontinue Qsymia immediately if pregnancy occurs. The Qsymia REMS program includes a Medication Guide, Healthcare Provider training, distribution through certified pharmacies, implementation system and a time table for assessments.

As part of the approval of Qsymia, Vivus must also conduct post-marketing studies. One study will assess the long-term treatment effect of Qsymia on the incidence of major adverse cardiovascular events in overweight and obese subjects with confirmed cardiovascular disease. The company will also conduct studies to assess the safety and efficacy of Qsymia for weight management in obese pediatric and adolescent subjects, studies to assess drug utilization and pregnancy exposure, a study to assess renal function, and animal and in vitro studies.

Implications of the approval of Belviq and Qsymia

The FDA’s approval of Belviq and Qsymia indicates that the FDA is more willing to make antiobesity drugs available to patients than it has been previously, even in the face of continuing concerns about long-term safety. Rather than rejecting these drugs, the FDA is handling its concerns about safety via post-marketing studies, and restricting distribution of the drugs. (Restricted distribution of the drugs may also help prevent their unregulated use for cosmetic weight-loss, as occurred with “Fen-Phen”.) Given the recent findings about the risk of birth defects with topiramate, the FDA is also employing a REMS designed to prevent the use of the drug by pregnant women.

Phase 2 and 3 studies of Belviq and Qsymia (although the two drugs were not compared head-to-head) indicate that Qsymia is much more efficacious than Belviq. At least some medical experts consider Qsymia to be the most effective oral antiobesity drug ever approved in the U.S.

Stock analysts forecast that the apparent greater efficacy of Qsymia is likely to give it a strong sales advantage over Belviq. Some analysts project that Qsymia’s annual worldwide sales may reach $2 billion by 2017. However, Arena has a Big Pharma marketing partner for Belviq, Eisai, while Vivus currently must market Qsymia on its own. This gives an advantage to Beviq. However, it is possible that Vivus might find a Big Pharma partner for Qsymia and its erectile dysfunction drug avanafil (Stendra), or the company might be acquired outright.

The long history of postmarking safety issues in the CNS-acting drug field, exemplified by fenfluramine/dexfenfluramine may be expected to discourage use of both Belviq and Qsymia by many physicians and patients, at least until one or both of these drugs shows a strong track record of safety. Third-party payers will also be expected not to cover either drug.

Conclusions

The approval of Qsymia by the FDA–just one month after the approval of lorcaserin–adds new impetus to the revival of the antiobesity drug market–including drug discovery and development, and the marketing of antiobesity agents. This includes approaches that work by increasing energy expenditure, rather than the usual approach of decreasing appetite by targeting the CNS. We discussed some of these novel approaches in our May 23, 2012 article on this blog.

The need for antiobesity agents is great, and with the fast accelerating incidence of obesity and its complications, the need is also accelerating. Moreover, our understanding of the pathogenesis of obesity is limited. Thus both continuing basic research and development of agents with novel mechanisms are sorely needed.

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18 July 2012

Cancer immunotherapy revisited

By Allan Haberman, Ph.D|2019-04-16T21:59:02+00:00July 18, 2012|Cancer, Drug Development, Drug Discovery, Immunology, Monoclonal Antibodies|

Macrophages attack a cancer cell

An article in the June 2012 issue of OncologyLive, authored by the publication’s senior editor, Anita T. Shaffer, reviews cancer immunotherapies now in late-stage clinical trials, and discusses the prospects for the field.

The article begins with a discussion of the recent renaissance of cancer immunotherapy, as exemplified by the April 2010 FDA approval of Dendreon’s Sipuleucel-T (APC8015, Provenge) and the March 2011 FDA approval of Ipilimumab [Medarex/Bristol-Myers Squibb’s (BMS’) Yervoy]. It then went on to discuss the exciting Phase 1 results with Medarex/BMS’ anti-PD-1 MAb, which we featured in the June 28, 2012 article on the Biopharmconsortium Blog.

But the bulk of the article was a discussion of the current late-stage (Phase 3) active immunotherapy pipeline. The article’s table lists 14 such agents. If one eliminates Cel-Sci/Teva’s Multikine (which is a mixture of cytokines), that leaves 13 agents, at least most of which can be described as therapeutic cancer vaccines. These products range from dendritic cell vaccines to tumor cell-based vaccines and viruses that encode tumor antigens.

For example, Argos Therapeutics‘ AGS-003 (Arcelis) is an autologous dendritic cell vaccine loaded with the patient’s own messenger RNA (mRNA). This vaccine is in Phase 3 clinical trials in patients with newly diagnosed metastatic renal cell carcinoma (mRCC). We mentioned Argos and its technology in our November 25, 2011 article on the late Ralph Steinman, MD, who had discovered the dendritic cell and elucidated its central role in the immune system. Dr. Steinman was a cofounder of Argos. Patient mRNA in Argos’ cellular immunotherapy product encode tumor antigens, which are expressed on the surface of the dendritic cells. The dendritic cells then potentiate the production of tumor antigen-specific T cells which attack the patient’s tumor.

According to a July 2 2012 company news release, AGS-003 is a fully personalized immunotherapy that preferentially targets mutated tumor antigens, which drive disease progression. Patient T cells recognize these antigens as foreign. This enables AGS-003 to direct a specific and potent anti-tumor immune response, without attacking normal tissues.

In a Phase 2 study of a combination of AGS-003 and sunitinib (Pfizer’s Sutent, the standard of care for mRCC), researchers demonstrated a statistically significant correlation between the number of anti-tumor T cells induced and overall survival in mRCC patients receiving AGS-003. Adding AGS-003 to sunitinib doubled overall survival for these patients compared to historical results for unfavorable risk patients treated with sunitinib alone. Over 50 percent of patients in the study survived longer than 30 months after initiating therapy, which is four times the expected rate for sunitinib.

Another type of cancer vaccine is based on modified cancer cells. In our Steinman article, this strategy is represented by BioSante’s GVAX cancer vaccines [now licensed by Aduro BioTech (Berkeley, CA)]. One such vaccine, GVAX Pancreas for pancreatic cancer (which is now in clinical trials) is based on human pancreatic cancer cell lines that have been engineered to secrete the immunostimulant granulocyte-macrophage colony-stimulating factor (GM-CSF), and have then been lethally irradiated. Since the most advanced GVAX products are in Phase 1 and Phase 2 clinical trials, GVAX was not covered in the OncologyLive article.

However, other more advanced immunotherapies, such as NewLink Genetics‘ HyperAcute Pancreas cancer immunotherapy (in Phase 3 trials), also consist of modified cancer cells. HyperAcute Pancreas consists of equal parts of two separate allogeneic pancreatic cancer cell lines engineered to express α-galactosidase (an enzyme that is not expressed by natural human pancreatic tumors).

Another type of cancer vaccine is based on viruses that encode tumor antigens. For example, Bavarian Nordic A/S’ PROSTVAC, a treatment for prostate cancer, is a sequentially dosed combination of vaccinia and fowlpox poxviruses that encode an altered, more immunogenic form of prostate-specific antigen (PSA) plus three immune enhancing costimulatory molecules ( B7.1, ICAM-1, and Lfa-3).

The late-stage immunotherapies listed in the table in the OncologyLive article include cancer vaccines that represent several design strategies other than the three mentioned here.

Some good news about sipuleucel-T

The OncologyLive article also referred to an abstract presented at the 2012 American Society of Clinical Oncology (ASCO) meeting, which suggests that the survival advantage for prostate cancer patients treated with sipuleucel-T was significantly greater than the 4.1-month benefit reported in the Phase 3 trial that led to approval of the agent. The analysis reported in this abstract indicates that the overall survival treatment benefit with sipilleucel-T ranged from 4.1 months to 7.8 months.

Conclusions

As illustrated by the number of late-stage cancer immunotherapies in development, as well as the approval of two drugs in 2010 and 2011, cancer immunotherapy is here to stay. One question in the use of such immunotherapies, as highlighted in the OncologyLive article, is how they will be integrated with such established modalities as cytotoxic chemotherapy, radiation therapy, and targeted cancer therapies.

Another factor is cost. A course of treatment with sipuleucel-T costs $93,000, and the cost of a course of treatment with ipilimumab is $120,000. However, as pointed out in the OncologyLive article, the total cost of treatment with other modalities that may continue for months or years may be higher. Nevertheless, the cost of cancer therapies, especially those that only increase overall survival by a few months, is a great concern to patients, physicians, and payers.

It must be remembered, however, that nearly all cancer therapies, when first introduced to the market, gave only slightly enhanced survival over older treatments. However, as oncologists learned how to use the therapies better (e.g., with changes in dosing, use in other groups of cancer patients, and/or use in combination therapies), numerous therapies eventually gave long-term remissions or even cures and proved to be cost-effective indeed.

Another issue with the cancer immunotherapy field, as pointed out in the OncologyLive article, is the difficulty of raising capital for cancer immunotherapy specialty companies. This is especially true in the current market, where most biotech companies have difficulty in raising capital. However, what venture capitalists and Big Pharma consider to be “premature technologies” or “unproven” emerging early-stage areas, as is usually the case, have particular difficulty in attracting investment.

Nevertheless, if and when additional late-stage cancer immunotherapy agents successfully complete Phase 3 trials and gain approval, this may demonstrate to investors that cancer immunotherapy has graduated from the premature-technology stage. In that case, cancer immunotherapy specialty companies may find it easier to attract capital, and large pharmaceutical companies may wish to acquire some of these companies. Since Big Pharma already is involved in developing such immunotherapies as anti-PD-1 and anti PD-1L, and ipilimumab is already a marketed Big Pharma drug, that should not be much of a stretch.

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