On January 10, 2022 InflaRx N.V. (Nasdaq: IFRX), a clinical-stage biopharmaceutical company developing anti-inflammatory therapeutics by targeting the complement system, reported a new pipeline program, INF904, an oral small molecule inhibitor of C5aR (Press release, InflaRx, JAN 10, 2022, View Source [SID1234598514]).

"Inhibition of the C5a/C5aR axis provides strong anti-inflammatory effects in a variety of diseases. Blockade of C5a using highly specific antibodies, such as vilobelimab, may offer a fast, effective, and safe way to control C5a-induced inflammation. In addition to this approach, inhibition of C5aR by oral small molecules may provide the ease of administration required for effective long-term treatment for more chronic inflammatory diseases. In INF904, we have discovered a small molecule C5aR inhibitor, which has shown best-in-class potential in preclinical studies. We believe that INF904 could become a powerful inflammation-fighting tool that is highly complementary to vilobelimab," said Prof. Renfeng Guo, Chief Scientific Officer and Founder of InflaRx.

InflaRx recently has been granted a composition of matter patent for INF904 and associated compounds by the US Patent and Trademark Office and has completed IND-enabling (preclinical) studies that demonstrated no obvious toxicological findings even in the highest dose groups in required GLP toxicity analyses. In these preclinical studies, oral INF904 showed higher plasma exposure in animals, including non-human primates, and improved inhibitory activity in a hamster neutropenia model compared to the marketed C5aR inhibitor. Anti-inflammatory therapeutic effects in several preclinical disease models were also demonstrated by INF904. Further, in contrast to the marketed C5aR inhibitor, in vitro experiments showed INF904 has substantially less inhibition of the cytochrome P450 3A4/5 (CYP3A4/5) enzymes, which play an important role in the metabolism of a variety of drugs, including glucocorticoids.

InflaRx expects to initiate a Phase I program in the second half of 2022 and plans to study INF904 in complement-mediated, chronic autoimmune and inflammatory diseases where oral administration is the preferred choice for patients.

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On January 10, 2022 Coherus BioSciences, Inc. ("Coherus", Nasdaq: CHRS) and Shanghai Junshi Biosciences Co., Ltd. ("Junshi Biosciences", HKEX: 1877; SSE: 688180) reported that Coherus has initiated the process to exercise its option to license JS006, Junshi Biosciences’ TIGIT-targeted antibody, in the United States and Canada, expanding the companies’ 2021 immuno-oncology collaboration agreement (Press release, Coherus Biosciences, JAN 10, 2022, View Source [SID1234598512]). Coherus will pay Junshi Biosciences $35 million upfront, up to $255 million in development regulatory and sales milestones, and an 18% royalty on net product revenue, subject to terms and conditions agreed between the parties. Closing of the transaction is expected to follow receipt of any applicable regulatory clearances. Antibodies blocking TIGIT (T cell immunoglobulin and ITIM domain) have shown potential for synergistic anti-tumor activity in combination with PD-1/PD-L1 inhibitors. In pre-clinical studies, JS006 has demonstrated excellent binding affinity and strong inhibition of the TIGIT pathway. Investigational new drug (IND) applications allowing clinical development of JS006 have been approved in Chinese Mainland and in the United States. A dose escalation, dose expansion clinical trial (NCT05061628) evaluating the safety, tolerability and pharmacokinetic properties of JS006 as monotherapy and in combination with PD-1 inhibitor toripalimab in patients with advanced solid tumors is ongoing.

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"TIGIT is a leading-edge immuno-oncology target with significant therapeutic potential across multiple major tumor types. The exercise of the option for JS006 marks the emergence of Coherus as an immuno-oncology development company with a rich clinical and preclinical pipeline of product candidates to drive long-term growth," said Denny Lanfear, CEO of Coherus. "We are making rapid progress on our objective to become a leading immuno-oncology company, and the development of toripalimab combinations with therapeutics addressing novel targets such as TIGIT will allow us to access future growing markets. While toripalimab + JS006 is the first novel combination in our pipeline, our internal analytic, protein science and bioinformatics capabilities have generated additional toripalimab combination candidates. The first of these proprietary product candidates is expected to enter human clinical trials in 2023."

"Blockade of the TIGIT pathway may be a crucial underlying mechanism for overcoming resistance to checkpoint inhibition. We believe the dual immuno-therapy approach of TIGIT with PD-1 could enhance PD-1 efficacy and create a new standard-of-care for multiple tumor types," said Theresa LaVallee, Ph.D., Chief Development Officer at Coherus. "We recently reported that our PD-1 inhibitor, toripalimab, in combination with chemotherapy, extends both progression free survival and overall survival in patients with advanced non-small cell lung cancer. We look forward to working with our Junshi Biosciences colleagues to build upon this efficacy signal and to evaluate the potential of the JS006 and toripalimab combination to bring new, more efficacious immuno-oncology treatments forward for patients."

"We are excited to extend our productive immuno-oncology collaboration with Coherus to include our anti-TIGIT monoclonal antibody JS006, after achieving several key milestones on toripalimab," said Dr. Ning Li, CEO of Junshi Biosciences. "Following our ‘In China, For Global’ corporate strategy, we are actively conducting global clinical R&D programs in China, the U.S., Southeast Asia and European countries. We are grateful for the joint effort from our pre-clinical as well as clinical teams at the company’s innovation centers in China and the U.S. We believe the collaboration with Coherus will strengthen the development and commercialization of our products in the U.S. and Canada."

"Since 2012, Junshi Biosciences has built a rich pipeline with complementary products in the area of immuno-oncology, which enable us to explore combination therapy of I-O drugs and combination of immunotherapy with other modalities, including traditional chemotherapy, radiotherapy, angiogenesis inhibitors and cytokine drugs, to provide patients with better treatment options," said Dr. Sheng Yao, Senior Vice President of Junshi Biosciences. "The combination of anti-TIGIT and anti-PD-1 is quite promising with a potential to not only increase patients’ response to I-O therapy, but also expand the beneficial patient population. We look forward to working together with Coherus to quickly advance the combination therapy of JS006 with toripalimab across multiple tumor types."

About JS006
JS006 is a recombinant humanized IgG4κ monoclonal antibody specifically against human TIGIT, developed independently by Junshi Biosciences. Including back-up candidates, the JS006 program encompasses molecules with silent and active Fc functions. According to the results of preclinical studies, JS006 can specifically block the TIGIT-PVR pathway. Expressed by T cells and NK cells, TIGIT can be engaged and activated by PVR family ligands highly expressed on tumor cells and suppressive immune cells to directly inhibit the killing effect of T cells and NK cells directed at tumor cells. A number of pre-clinical and clinical studies have showed that activation of the TIGIT pathway could be a crucial underlying mechanism for the resistance to PD-1 blockade therapy. Combination of TIGIT and PD-1/PD-L1 antibodies showed a synergistic potential to enhance antitumor response to overcome anti-PD-1 resistance and broaden the cancer patient population that can benefit from immunotherapy.

In early 2021, JS006 was approved for clinical trials in both China and the United States. In the same year, Junshi Biosciences commenced a phase I trial to evaluate the safety and tolerability of JS006 as monotherapy and in combination with toripalimab in patients with advanced tumors who have failed standard therapies. Coherus and Junshi Biosciences are planning late-stage clinical development of JS006 in combination with toripalimab in North America.

About toripalimab
Toripalimab is an anti-PD-1 monoclonal antibody developed for its ability to block PD-1 interactions with its ligands, PD-L1 and PD-L2, and for enhanced receptor internalization (endocytosis function). Blocking PD-1 interactions with PD-L1 and PD-L2 promote the immune system’s ability to attack and kill tumor cells.

More than thirty company-sponsored toripalimab clinical studies covering more than fifteen indications have been conducted globally, including in China, the United States, Southeast Asia, and European countries. Ongoing or completed pivotal clinical trials evaluating the safety and efficacy of toripalimab cover a broad range of tumor types including cancers of the lung, nasopharynx, esophagus, stomach, bladder, breast, liver, kidney and skin.

In China, toripalimab was the first domestic anti-PD-1 monoclonal antibody approved for marketing (approved in China as TUOYI). Currently, there are 4 approved indications for toripalimab in China:

unresectable or metastatic melanoma after failure of standard systemic therapy;
recurrent or metastatic nasopharyngeal carcinoma (NPC) after failure of at least two lines of prior systemic therapy;
locally advanced or metastatic urothelial carcinoma that failed platinum-containing chemotherapy or progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy;
in combination with cisplatin and gemcitabine as the first-line treatment for patients with locally recurrent or metastatic NPC.
The first three indications have been included in the National Reimbursement Drug List (NRDL) (2021 Edition). Toripalimab is the only anti-PD-1 monoclonal antibody included in the NRDL for melanoma and NPC.

In addition, two supplemental New Drug Applications (NDAs) for toripalimab are currently under review by the National Medical Products Administration (NMPA) in China:

in combination with chemotherapy as the first-line treatment of patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC).
in combination with chemotherapy as the first-line treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) with no EGFR or ALK sensitizing mutations.
In the United States, the FDA has granted priority review for the toripalimab biologics license application (BLA) for the treatment of recurrent or metastatic NPC, an aggressive head and neck tumor which has no FDA-approved immuno-oncology treatment options. The FDA has assigned a Prescription Drug User Fee Act target action date for April 2022 for the toripalimab BLA. The FDA granted Breakthrough Therapy designation for toripalimab in combination with chemotherapy for the first-line treatment of recurrent or metastatic NPC in 2021 as well as for toripalimab monotherapy in the second or third-line treatment of recurrent or metastatic NPC in 2020. Additionally, the FDA has granted Fast Track designation for toripalimab for the treatment of mucosal melanoma and orphan drug designation for the treatment of esophageal cancer, NPC, mucosal melanoma and soft tissue sarcoma. In 2021, Coherus in-licensed rights to develop and commercialize toripalimab in the United States and Canada. Coherus and Junshi Biosciences plan to file additional toripalimab BLAs with the FDA over the next three years for multiple other cancer types.

On January 10, 2022 HiFiBiO Therapeutics, a multinational clinical-stage biotherapeutics company, reported that the U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug (IND) application for HFB301001 (Press release, HiFiBiO Therapeutics, JAN 10, 2022, View Source [SID1234598511]). HFB301001 is a second-generation, potential best-in-class fully human IgG1 OX40 agonistic antibody with an optimized pharmacological profile .

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"The FDA’s clearance of our IND for HFB301001 further strengthens our position as a clinical stage therapeutics company," said co-founder and CEO of HiFiBiO Therapeutics, Liang Schweizer, Ph.D. "I am excited to demonstrate that our single cell-powered DIS platform can potentially overcome the challenges of well-known targets like OX40, in addition to discovering novel drugs for new targets like TNFR2."

"We were excited to find that unlike first generation anti-OX40 antibodies, the agonistic activity of HFB301001 is further enhanced in the presence of the endogenous ligand OX40L" shared Francisco Adrián, Ph.D., CSO of HiFiBiO Therapeutics. "HFB301001’s unique binding epitope minimizes OX40 receptor downregulation and demonstrates stronger anti-tumor activity than a benchmark antibody in a human OX40 knock-in mouse tumor model."

"The planned Phase I clinical study will consist of a dose escalation followed by expansion cohorts in selected solid tumors identified through our DISTM platform," said Luigi Manenti, M.D., CMO of HiFiBiO Therapeutics. "The comprehensive single-cell biomarker approach using our DIS platform can significantly strengthen the HFB301001 clinical development plan. We hope to use these innovative biomarkers to select patients who may benefit the most from HFB301001 treatment."

On January 10, 2021 Theseus Pharmaceuticals, Inc. (Theseus) (NASDAQ: THRX), a biopharmaceutical company focused on improving the lives of cancer patients through the discovery, development and commercialization of transformative targeted therapies, reported that the first patient has been treated in the Phase 1 portion of Theseus’ ongoing Phase 1/2 study to evaluate lead candidate, THE-630, in patients with advanced gastrointestinal stromal tumors (GIST) (Press release, Theseus Pharmaceuticals, JAN 10, 2022, View Source [SID1234598510]).

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THE-630 is a pan-variant inhibitor of the receptor tyrosine kinase KIT. It is designed for patients with advanced GIST whose cancer has developed resistance to earlier lines of therapy by accruing mutations that render those therapies ineffective. In GIST, these mutations occur most often in the KIT protein, where a patient can have multiple KIT mutations simultaneously, leading to complex disease heterogeneity. Pan-variant inhibitors like THE-630 are single therapeutic molecules designed to inhibit all known, clinically relevant mutations of a target protein to address the problem of disease heterogeneity that contributes to treatment resistance. In preclinical studies, THE-630 demonstrated potent in vitro and in vivo activity against all major classes of KIT activating and resistance mutations in GIST. Moreover, THE-630 achieved predicted pan-variant KIT inhibitory blood concentrations at tolerable doses and was associated with significant anti-tumor activity.

"Patients with unresectable or metastatic GIST who have exhausted standard therapies have limited treatment options and poor clinical outcomes. GIST disease progression remains largely KIT-dependent even after multiple lines of therapy, and a significant unmet need remains for these patients," said Suzanne George, M.D., Clinical Director, Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute. "I am excited to work with Theseus on this first-in-human trial of THE-630, and I look forward to evaluating its clinical potential to address the needs of patients with advanced GIST."

"The initiation of our Phase 1/2 trial in patients with previously-treated advanced GIST is an important milestone as we begin to characterize THE-630 in the clinic," said David Kerstein, M.D., Chief Medical Officer at Theseus. "We believe THE-630 has a differentiated profile of pan-variant activity against KIT and we look forward to exploring a number of GIST settings where pan-variant inhibition may translate into meaningful clinical benefit–from the fifth-line, where no standard therapies exist, to earlier lines of therapy, such as the second-line, where current standard of care yields less than optimal outcomes."

About the Phase 1/2 study and clinical development plan

Study THE630-21-101 is a Phase 1/2 open label, multicenter, first-in-human dose-escalation and expansion study designed to evaluate the safety, pharmacokinetics, and anti-tumor activity of oral THE-630 (NCT Number: NCT05160168). The study is expected to be conducted in two parts: a dose escalation phase, followed by an expansion phase. The patient population of the initial dose escalation phase (Phase 1) of the trial will include patients with unresectable or metastatic GIST who had disease progression on or are intolerant to imatinib therapy and have also received at least one of the following: sunitinib, regorafenib, ripretinib, or avapritinib. The primary objective of the dose escalation phase is to determine the safety profile of THE-630, including the dose limiting toxicities, maximum tolerated dose, and the recommended Phase 2 dose.

Once a recommended dose has been determined in the escalation phase, the expansion phase (Phase 2) will enroll patients with unresectable or metastatic GIST into cohorts defined by prior therapy from a

second-line population to a fifth-line population. The primary objective of the expansion phase is to evaluate the anti-tumor activity of THE-630 in these GIST patient populations.

Data from the Phase 1/2 clinical trial is expected to inform further clinical development of THE-630 including the design of an initial registrational trial in fifth-line GIST, where there is currently no available therapy and therefore a significant unmet need. THE-630 is also expected to be evaluated in second-line GIST, where a pan-KIT inhibitor with activity against all major classes of activating, or cancer-causing, and resistance mutations has the potential to deliver meaningful clinical benefit over the current standard of care.

Initial data from the Phase 1 portion of the clinical trial is expected to be presented at a scientific meeting in the first half of 2023.

About GIST

GIST is the most common sarcoma of the gastrointestinal tract with an estimated 4,000 to 6,000 new cases diagnosed in the United States each year. Approximately eighty percent of GIST cases are driven by mutations that activate the kinase activity of the receptor tyrosine kinase KIT, and up to ninety percent of all relapse cases are driven by secondary resistance mutations in KIT.

On January 10, 2021 BioCryst Pharmaceuticals, Inc. (Nasdaq:BCRX) reported preliminary, unaudited ORLADEYO (berotralstat) revenue for the fourth quarter and full year 2021 and provided new guidance for full year 2022 ORLADEYO net revenue and expected peak ORLADEYO sales (Press release, BioCryst Pharmaceuticals, JAN 10, 2022, View Source [SID1234598509]).

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"Following 12 months of a successful launch through a global pandemic, we have a clear picture of the continued commercial trajectory for ORLADEYO based on a very attractive product profile, leading to strong patient demand to switch from injectable therapies to our oral, once-daily medicine, with 70 percent patient retention through the first year. Building on our substantial 2021 patient base, we are confident that ORLADEYO will achieve no less than $250 million of net revenue in 2022 and that ORLADEYO will become the market leader as the most prescribed prophylactic therapy with peak sales of $1 billion," said Jon Stonehouse, president and chief executive officer of BioCryst.

Fourth Quarter 2021 (Q4 2021) ORLADEYO Launch Dynamics

Preliminary, unaudited ORLADEYO net revenue in Q4 2021 was $45.6 million. Preliminary, unaudited ORLADEYO net revenue for full year 2021 (FY 2021) was $122 million.

New patient demand for ORLADEYO remains strong and consistent, with a similar number of new patients added in Q4 2021 as in each of the previous three quarters of the year. Patients switching from other prophylactic therapies and acute-only therapy continue to drive the launch. More than half of patients new to ORLADEYO since launch had a previous prophylactic medicine prior to ORLADEYO and most of the remainder were from acute-only treatment.

Most patients are well-controlled on ORLADEYO and remain on therapy. Approximately 70 percent of patients starting ORLADEYO, including those switching from injectable prophylaxis, remain on ORLADEYO in the first year.

ORLADEYO is now covered by all major payors and national and regional pharmacy benefit managers, which will lead to more patients being reimbursed quickly.

The ORLADEYO prescriber base continues to grow significantly. The number of new physicians prescribing ORLADEYO in Q4 2021 was similar to the number added in Q3 2021. In market research, 60 U.S. physicians, who treat an average of seven HAE patients each, reported that they expect to double their use of ORLADEYO, and that ORLADEYO will become their most prescribed prophylactic treatment in the next 12 months.
"We expect ORLADEYO revenues in 2022 to more than double in our second year of launch as we benefit from a full year of reimbursement and continued strong demand from patients and physicians. ORLADEYO is transforming the lives of HAE patients, which is why ORLADEYO is on a trajectory to become the market leader in HAE prophylaxis," said Charlie Gayer, chief commercial officer of BioCryst.

Pipeline Update: BCX9930 Pivotal Trials in PNH Now Enrolling

BioCryst is currently enrolling patients in two global pivotal trials, REDEEM-1 and REDEEM-2, with the company’s oral Factor D inhibitor, BCX9930 (500 mg bid), in patients with paroxysmal nocturnal hemoglobinuria (PNH). The company also has begun screening patients in a proof of concept (PoC) basket trial of BCX9930 (500 mg bid) in patients with C3 glomerulopathy (C3G), IgA nephropathy (IgAN) and primary membranous nephropathy (PMN).

BioCryst plans to further advance and expand its Factor D program over the next two years by achieving the following:

Complete and report data from REDEEM-1 and REDEEM-2
Prepare to submit regulatory approval filings in PNH
Complete the renal PoC basket trial and advance to pivotal trials in C3G, IgAN and PMN
Commence PoC trials in other complement-mediated diseases
"Following the discovery, development and commercialization of ORLADEYO, the BioCryst team plans to repeat this success as we leverage our platform to bring new oral medicines to patients suffering from other rare diseases. BCX9930 is especially exciting because the clinical data we have reported so far provides confidence that we can help patients in PNH, and across many complement-mediated diseases, with this pipeline in a molecule," said Dr. Helen Thackray, chief research and development officer of BioCryst.

Presentation Today at 40th Annual J.P. Morgan Healthcare Conference

Today at 9:45 a.m. ET, the company will present at the 40th Annual J.P. Morgan Healthcare Conference, which is being conducted as a virtual event. Links to a live audio webcast and replay of the presentation may be accessed in the Investors section of BioCryst’s website at https://www.biocryst.com/.

About ORLADEYO (berotralstat)
ORLADEYO (berotralstat) is the first and only oral therapy designed specifically to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients 12 years and older. One capsule of ORLADEYO per day works to prevent HAE attacks by decreasing the activity of plasma kallikrein.

U.S. Indication and Important Safety Information

INDICATION
ORLADEYO (berotralstat) is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older.

Limitations of use
The safety and effectiveness of ORLADEYO for the treatment of acute HAE attacks have not been established. ORLADEYO should not be used for the treatment of acute HAE attacks. Additional doses or dosages of ORLADEYO higher than 150 mg once daily are not recommended due to the potential for QT prolongation.

IMPORTANT SAFETY INFORMATION
An increase in QT prolongation was observed at dosages higher than the recommended 150 mg once-daily dosage and was concentration dependent.

The most common adverse reactions (≥10 percent and higher than placebo) in patients receiving ORLADEYO were abdominal pain, vomiting, diarrhea, back pain, and gastroesophageal reflux disease.

A reduced dosage of 110 mg taken orally once daily with food is recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) and in patients taking chronically administered P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) inhibitors (eg, cyclosporine).

Berotralstat is a substrate of P-gp and BCRP. P-gp inducers (eg, rifampin, St. John’s wort) may decrease berotralstat plasma concentration, leading to reduced efficacy of ORLADEYO. The use of P-gp inducers is not recommended with ORLADEYO.

ORLADEYO at a dose of 150 mg is a moderate inhibitor of CYP2D6 and CYP3A4. For concomitant medications with a narrow therapeutic index that are predominantly metabolized by CYP2D6 or CYP3A4, appropriate monitoring and dose titration is recommended. ORLADEYO at a dose of 300 mg is a P-gp inhibitor. Appropriate monitoring and dose titration is recommended for P-gp substrates (eg, digoxin) when coadministering with ORLADEYO.

The safety and effectiveness of ORLADEYO in pediatric patients <12 years of age have not been established.

There are insufficient data available to inform drug-related risks with ORLADEYO use in pregnancy. There are no data on the presence of berotralstat in human milk, its effects on the breastfed infant, or its effects on milk production.