American Home Products (AHP) puts research and development pipeline in spotlight

Scrip via Individual Inc. : ** NOTE: TRUNCATED STORY **

American Home Products has presented an extensive and unprecedented overview of its R&D pipeline to US analysts.

Long known for its reluctance to discuss such matters, AHP is now trying to rebuild its image as a top-tier pharmaceutical company. The R&D review, presented at its Pearl River, New York campus, summarised its efforts in six key areas, testifying to a significantly increased commitment to new product development, with more than 60 compounds in the pipeline.

new product launches

The company expects to launch six new products in the US this year: a single-tablet version of the HRT, Prempro/Premphase; the once-daily naproxen, Naprelan; the hyperimmunoglobulin, RespiGam, for prevention of RSV disease in infants; the obesity agent, Redux (dexfenfluramine), for which final labelling negotiations are underway; the low molecular weight heparin, Normiflo (ardeparin sodium); and the non-narcotic analgesic, Duract (bromfenac sodium). Expanded US claims are expected for Lodine (etodolac) in rheumatoid arthritis, and Zosyn (tazobactam/piperacillin) in nosocomial pneumonia.

AHP spent $1.05 billion on pharmaceutical R&D in 1995, more than double that in 1990. In the five years, it has added more than one million square feet of additional laboratory space. It has 21 product candidates in pre-Phase II stages of development. An overview of the later stage pipeline is given in the inset box.

(1) in collaboration with Cygnus; (2) under development by Genetics Institute; (3) joint venture with Roussel Uclaf.

sales, profits

AHP's pharmaceutical sales rose by 45% last year to about $7.5 billion, but fell slightly in the US because of changes in the timing of trade incentives on certain products. Gross income from healthcare products was $2.9 billion, up by 57%, while SG&A expenses rose by the same percentage to almost $5 billion (see Scrip No 2099, p 8 for further details of AHP's 1995 results).

women's health

AHP aims to maintain its number one position in women's health by adding new hormone products and line extensions, pursuing new indications, and licensing in novel compounds, according to senior vice-president for clinical research Joseph Pittelli.

It submitted a US marketing application for levonorgestrel/EE low dose oral contraceptive on March 26th, months ahead of schedule, and plans to develop even lower dosage forms of this product. Two other products - a levonorgestrel contraceptive implant and a 17-beta estradiol patch for hormone replacement therapy - are awaiting US approval and another seven are in Phase III.

The company is investigating whether its flagship oestrogen product, Premarin, may ameliorate or delay the onset of dementia in Alzheimer's disease. The FDA has approved a six-year study protocol involving 8,000 patients and has indicated that, if positive, this single study could provide sufficient data for approval.

Two major trials are underway to expand indications for Prempro/Premphase. The HERS study will assess Prempro in reducing the risk of coronary heart disease, while the HOPE study will look at the lowest effective combination dose to reduce bone mineral loss and the risk of endometrial hyperplasia.

The novel 19-norpregnane derivative, trimegestone, is in Phase III studies in hormone replacement and oral contraception under a worldwide licensing agreement with Roussel Uclaf. Trimegestone reportedly shows superior potency to currently marketed products and lacks undesirable androgenic, estrogenic, glucocorticoid and mineralocorticoid activities, with very little effect on blood glucose and lipid levels. It has US patent protection until 2004.

CNS

AHP's noradrenaline and serotonin reuptake inhibitor, Effexor (venlafaxine), is now approved for depression in 27 countries, with registrations pending in a further 21. It will be launched in 12 countries this year. In its first year on the US market, it had sales of more than $150 million. The compound is patent protected until 2007.

Ongoing research with Effexor is examining its rapid onset of action. AHP is allowed to use a "fast-acting" claim in 17 countries and hopes to add this claim to the US labelling. While most antidepressants take two or three weeks to take effect, Effexor is often effective in its first week, according to Dr Albert Derivan, assistant vice-president for clinical R&D.

The company is also investigating a new indication, generalised anxiety disorder in non-depressed patients. Phase III trials have excluded depressed patients to demonstrate activity in anxiety independent of the drug's antidepressant effects. AHP plans to complete its registration dossier in this indication by the third quarter of 1997.

The worldwide market for anxiolytics is expected to reach $3.7 billion by 2001.

An NDA filing for extended-release Effexor, with improved efficacy, is planned this year. A sustained-release version is in development using Alza's osmotic pump technology to provide constant concentrations over 24 hours, with the NDA expected to be filed in 2000. Other potential indications for Effexor include mood disorders in women (premenstrual syndrome, postpartum and postmenopausal depression), attention deficit disorder, pain syndromes, and use in geriatric populations.

Dr Derivan said that the company's new hypnotic for insomnia, zaleplon, showed significant advantages over currently available hypnotics. It does not exhibit next-day hangover effects or rebound insomnia, and no withdrawal symptoms have been observed after six months' treatment. With a one-hour half-life, zaleplon does not alter normal sleep architecture, and does not require patients to remain in bed for the full eight hours needed with other hypnotics.

The market for insomnia is estimated at $320 million in the US, and $1.4 billion worldwide.

immunology/oncology

The new immunosuppressant, Rapamune (sirolimus, formerly called rapamycin), has potent effects on lymphocytes and vascular smooth muscle cells. Unlike ciclosporin and tacrolimus, it blocks the amplification process for T-cells synthesised via both IL-2 and non-IL-2 pathways. It does not have the nephrotoxic, neurotoxic, and hepatotoxic side-effects that limit treatment with ciclosporin, said senior director of clinical R&D Dr Joseph Camardo.

Phase II data confirm Rapamune's safety and efficacy in renal transplantation, and AHP believes Rapamune will ultimately replace ciclosporin in this indication. Other applications include liver, bone marrow and heart transplants, autoimmune diseases, and restenosis.

cardiovascular/metabolic

Dr Betty Riggs, senior director of clinical R&D, said that the results of the EMIAT and CAMIAT studies, reported at the American College of Cardiology (Scrip No 2116, p 18), form the basis of a supplemental NDA for the Class III anti-arrhythmic, Cordarone (amiodarone, licensed from Sanofi), for reduction of arrhythmic mortality in post-MI patients. Two studies are ongoing in North America to determine the efficacy of Cordarone IV in out-of-hospital cardiac arrest, administered by paramedics during resuscitation. Positive results would support the addition of Cordarone to the Advanced Cardiac Life Support Guidelines, she said.

The drug's unique pharmacokinetics may make it difficult to conduct bioequivalence studies, potentially reducing the risk of generic competition. This is also a therapeutic area where physicians are often reluctant to use generics, Dr Riggs noted.

The angiotensin II receptor antagonist, tasosartan, is seen as a fast-track follow-on to Merck & Co's Cozaar (losartan), which established this new class of antihypertensives. Tasosartan offers once-daily dosing, excellent 24-hour blood pressure control, and a side-effect profile similar to placebo, AHP says.

AHP has put tasosartan through a swift, four-year development programme, and expects to file an NDA this year. At a pre-NDA meeting with the FDA, the agency raised no issues which might question approvability, Dr Riggs said. The US patent for tasosartan extends until 2009, while in Europe it is protected until 2012.

The obesity treatment, Redux (dexfenfluramine), will be marketed for patients with significant obesity (body mass index > 30kg/mg(2)). AHP hopes to target those most likely to respond well to treatment over the long term. The INDEX study found that short-term results are predictive of long-term response - 60% of patients who lose four pounds in the first month will lose at least 10% of body weight in 12 months.

AHP says it wants Redux to be used only when medically necessary and is preparing to limit initial uptake and build up its market gradually. It will seek labelling which limits use to those with significant obesity, in conjunction with a weight reduction programme. Redux has been designated approvable by the FDA and, in labelling discussions, the agency has not sought any limitations on the duration of use; full approval is expected this year.

vaccines

AHP is the leading vaccine company in the US, and aims to move from number five to number three in Europe by 2000, according to Wyeth-Lederle Vaccines & Pediatrics president Dr Ronald Saldarini. With the merger of Cyanamid's Lederle-Praxis unit into AHP, the company now has a global vaccine R&D capability.

Rotashield/Rotamune, now in Phase III targets the rotavirus vaccine, a significant cause of infant mortality associated with gastroenteritis in developing countries, and a major nosocomial pathogen. It is being developed for co-administration with oral polio vaccine, in three doses for infants aged six-30 weeks.

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AHP Product Pipeline
(by US status)
Product                  Indication                    Int'l Status
NDA/PLA filed
Duract (bromfenac Na)    acute and chronic pain          n/a
Lodine (etodolac) 500mg  osteoarthritis                  n/a
Lodine RA                rheumatoid arthritis            registered
Lodine XL                once-daily, osteo- and          registered
                          rheumatoid arthritis
Lyrelle Patch            HRT for vasomotor symptoms in   EU filed
 (17-beta estradiol)      menopause, 3.5 days
Normiflo (ardeparin      prophylaxis of deep vein thrombosis  n/a
 Na)                      and pulmonary embolism in knee
                          surgery
Redux (dexfenfluramine)  obesity                         n/a
Zosyn (tazobactam/
 piperacillin)           nosocomial pneumonia            registered
levonorgestrel implant   contraceptive                   EU filed
levonorgestrel/EE        oral contraceptive              Phase III
Phase III
Acel-Imune               DTaP vaccine                    Phase III
Alredase (tolrestat)     adjunct to                      registered
                         hypoglycaemics/insulin
                          to prevent diabetic peripheral
                          neuropathy, retinopathy and
                          nephropathy
Effexor XR (venlafaxine) once-daily antidepressant,      Phase III
                          anxiolytic
ERT Patch(1)             HRT for vasomotor symptoms in   Phase III
 (17-beta estradiol)      menopause, 7 days
gestodene/EE             oral contraceptive              Phase III
GPA-748                  oral growth hormone releasing   Phase III
                          peptide
Leukine (sargramostim)   prevention of neutropenia in    n/a
                          chemotherapy (PLA filed),
                          post-operative infections
                          and infections in low weight
                          babies (Phase III), and HIV
                          (Phase II)
Neumega (rhIL-11)(2)     chemotherapy-induced            Phase III
                          thrombocytopenia
                         inflammatory bowel disease and  Phase I/II
                         chemotherapy-induced mucositis
                         (Phase I/II)
Novantrone               hormone refractory prostate
 (mitoxantrone)           cancer                         Phase III
                         metastatic breast cancer        registered
                         non-Hodgkin's lymphoma
                         (Phase I/II)                    registered
pneumococcal conjugate   prevention of pneumococcal      Phase III
 vaccine                  diseases
Prempro (estrogen/       secondary prevention of cv      Phase III
 progestin)               disease
Rapamune (sirolimus)     immunosuppression in organ      Phase III
                          transplants
rDNA Factor IX(2)        haemophilia B; blood clotting   Phase III
                          factor
Rotashield/Rotamune      oral rotavirus vaccine          Phase III
Suprax (cefixime)        sinusitis                       n/a
tasosartan               once-daily angiotensin II       Phase III
                          antagonist for hypertension
tasosartan/HCTZ          once-daily                      Phase III
                          antihypertensive/diuretic
Tetracel                 DTaP/H influenzae B vaccine     Phase III
trimegestone/17-beta     HRT for vasomotor symptoms and  Phase III
 estradiol(3)             prevention of osteoporosis
Tri-Minulet/Minulet      oral contraceptives             registered
 (gestodene)
zaleplon                 non-benzodiazepine              Phase III
                          sedative/hypnotic
Phase II
adatanserin              non-benzodiazepine anxiolytic   Phase II
ARI-509                  aldose reductase inhibitor for  Phase II
                          diabetic complications
rhBMP-2(2)               bone repair and regeneration    Phase II
BTA-243                  beta-3 agonist for chronic      Phase II
                          obesity
Effexor XL (OROS)        improved formulation,           Phase II
                          once-daily (venlafaxine)
                          antidepressant
Gestodene/17 beta        oral contraceptive              Phase II
 estradiol
rhIL-12(2)               immunomodulator in              Phase II
                          cancer/AIDS/hepatitis
meningococcal conjugate  prevention of meningococcal     Phase II
 vaccine                  systemic type C disease
PDA-641                  phosphodiesterase inhibitor for Phase II
                          asthma
RSV subunit vaccine      RSV-mediated lower respiratory  Phase II
                          disease
S-TNR-R (tumour          rheumatoid arthritis            Phase II
 necrosis factor receptor)